Dopamine d2 receptor ligands

ABSTRACT

The present invention relates to novel dopamine D2 receptor ligands. The invention further relates to functionally-biased dopamine D2 receptor ligands and the use of these compounds for treating or preventing central nervous system and systemic disorders associated with dysregulation of dopaminergic activity.

RELATED APPLICATIONS

The present application is a continuation of U.S. Ser. No. 15/537,741,filed Jun. 19, 2017, which is a national stage filing under 35 U.S.C. §371 of international PCT application, PCT/US2015/066928, filed Dec. 18,2015, which claims priority under 35 U.S.C. § 119(e) to U.S. provisionalpatent application, U.S. Ser. No. 62/094,670, filed Dec. 19, 2014, eachof which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel ligands of dopamine D2 receptors,in particular, functionally selective ligands of dopamine D2 receptors.The invention also relates to the use of these compounds in treating orpreventing central nervous system disorders as well as systemicdisorders associated with dopamine D2 receptors.

BACKGROUND OF THE INVENTION

G-protein-coupled receptors (GPCRs), also known as 7-transmembranereceptors, are the single largest class of drug targets, with more than800 members in the human genome (Lefkowitz, Trends in PharmacologicalSciences (2004), 413). Dopamine receptors represent prototypic examplesof GPCRs that mediate neurotransmission (Missale et al., PhysiologicalReviews (1998), 189). Dopamine is a monoamine neurotransmitter thatexerts its action on neuronal circuitry via dopamine receptors. Asdopaminergic innervations are most prominent in the brain, dopaminergicdysfunction can critically affect vital central nervous system (CNS)functions, ranging from voluntary movement, feeding, reward, affection,sleep, attention, working memory and learning (Carlsson, Science (2001),1021, Beaulieu et al., Pharmacological Reviews (2011), 182). Apart fromCNS functions, dopamine is also involved in important physiologicalroles such as the regulation of olfaction, cardiovascular functions,sympathetic regulation, hormonal regulation, retinal processes, immunesystem and renal function. Dysregulation of dopaminergicneurotransmission has been associated with multiple neurological andpsychiatric conditions such as Parkinson's disease, Huntington'sdisease, attention deficit hyperactivity disorder (ADHD), mood disordersand schizophrenia (Carlsson, Science (2001), 1021), as well as varioussomatic disorders such as hypertension and kidney dysfunction (Missaleet al., Physiological Reviews (1998), 189, Beaulieu et al.,Pharmacological Reviews (2011), 182).

With the complex array of critical cellular functions mediated bydopamine receptors, and the multilevel interactions that are known tooccur between dopamine and other extracellular messengers in thesignaling pathways, there remains a need to better managedopamine-related pathologic conditions by precise targeting ofpost-receptor intracellular signaling modalities, either directly orthrough ligand-biased signaling pharmacology.

As drug targets, GPCRs known to mediate dopamine functions can bebroadly classified into D1 and D2 class receptors. D1 class receptors(D1R and D5R) are mostly coupled to Gαs and positively regulate theproduction of second messenger cAMP and the activity of protein kinase A(PKA) (Missale et al., Physiological Reviews (1998), 189). D2 classreceptors (D2R, D3R and D4R) couple to Gαi/o, downregulating cAMPproduction and PKA activity (Missale et al., Physiological Reviews(1998), 189). Additionally, D2 class dopamine receptors also modulateintracellular Ca²⁺ levels, resulting in changes in activity of Ca²⁺regulated signaling proteins such as protein phosphatase calcineurin(Nishi et al., J. Neurosci., 1997, 17, 8147).

D2 class dopamine (D2R) receptors are presently the best-establishedtargets for antipsychotic drugs. Recent studies suggest that β-arrestin2 deficiency in mice results in reduction of dopamine-dependentbehaviours (Beaulieu et al., Cell (2005), 261). The connection betweenβ-arrestin 2 and dopamine-associated behaviours suggests that β-arrestin2 could be a positive mediator of dopaminergic synaptic transmission anda potential pharmacological target for dopamine-related psychiatricdisorders (Beaulieu et al., Cell (2005), 261).

Currently, all clinically marketed antipsychotics modulate dopamine bytargeting D2R either as antagonists/inverse agonists (first- andsecond-generation antipsychotics, for example, chlorpromazine,clozapine) or partial agonists (third-generation antipsychotics, witharipiprazole as the sole example of this ligand class in the clinic).Antagonism of dopamine D2 receptor/β-arrestin 2 interaction has beenfound to be a common property of clinically-effective antipsychotics(Masri et al., Proceedings of the National Academy of Sciences of theUnited States of America (2008), 13656).

Structure-functional selectivity relationship studies ofβ-arrestin-biased dopamine D2 receptor agonists, based on thearipiprazole scaffold, have been conducted (Chen et al., Journal ofMedicinal Chemistry (2012), 7141, Roth et al., US 2013/0137679, Shonberget al., Journal of Medicinal Chemistry (2013), 9199). Knownantipsychotics, even those that share a common mechanistic pathway suchas haloperidol, clozapine, and risperidone, show highly diverse effectson D2R/G protein signaling and are not selective across GPCR receptors.There remains a lack of clinical drug candidates that offer highlyfunctionalized targeting of dopamine D2 receptors that improve theclinical efficacy of antipsychotics, while at the same time limiting theundesirable side effects associated with D2-dopaminergic activity.

Selectively antagonizing the β-arrestin pathway at the D2 receptor couldbe sufficient to produce an antipsychotic effect, while at the sametime, reduce potential side effects that could arise from antagonizingthe cAMP pathway. Modulation of the β-arrestin-2 dependent pathway couldlead to modulation of AKT and GSK3β target genes (Beaulieu et al.,Frontiers in molecular neuroscience (2011), 38). Development ofcompounds with cAMP biased agonist or antagonist or β-arrestin biasedagonist or antagonist activity could offer a functionally selectivemeans to modulate or treat dopamine-associated disorders, includingParkinson's disease, Huntington's disease, mood disorders,schizophrenia, attention deficit hyperactivity disorder (ADHD), restlesslegs syndrome (RLS), pituitary disorders such as pituitary adenoma orpituitary tumor (prolactinoma) or endocrine disorders, e.g.,galactorrhea. Further, development of ligands that exhibit functionalselectivity as agonists, antagonists, and partial agonists, as well asselectivity against other GPCRs, allows modulation of activity at thedopamine D2 receptors to be more finely-tuned to increase selectivityand hence clinical efficacy and safety in treatment. By increasingselectivity at dopamine D2 receptors while minimising undesirableside-effects, drugs in this category would also offer greater successpotential with patient acceptance and compliance.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds that modulate dopamineD2 receptors. In particular, compounds of the present invention showfunctional selectivity at the dopamine D2 receptors and exhibitselectivity downstream of the D2 receptors, on the β-arrestin pathwayand/or on the cAMP pathway. Compounds of the present invention exhibitdifferent activity profiles either as agonist, antagonist, inverseagonist, or partial agonist. As these compounds are functionallyselective downstream of the D2 receptors, they offer more selectivityand functionality in treatment of diseases or disorders in whichdopamine plays a role, such as central nervous system disordersassociated with D2 receptors, while minimizing potential associated sideeffects. Use of β-arrestin biased D2 receptor antagonists whichselectively antagonize the β-arrestin pathway may offer a means to treatpsychotic disorders while also minimizing potential undesirableside-effects associated with D2 receptor activity. Similarly, biased D2receptor agonists which selectively activate either the β-arrestinpathway or the cAMP pathway may also be advantageous in treatment ofdisorders associated with dopamine receptors, such as Parkinson'sdisease, ADHD and restless leg syndrome or an endocrine disorder, e.g.,galactorrhea, with fewer side-effects.

The present invention provides a compound having Formula I:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein each ofthe variables is defined and illustrated in detail herein.

The present invention also provides a pharmaceutical compositioncomprising a compound of the invention or a pharmaceutically acceptablesalt, stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, and one or more pharmaceutically acceptable excipients orcarriers.

The present invention also provides a method of modulating D2 receptoractivity by administering a selective β-arrestin antagonist or apharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof.

The present invention also provides a method of modulating D2 receptoractivity by administering a compound which is a β-arrestin antagonistand a cAMP agonist, or a pharmaceutically acceptable salt, stereoisomer,racemate, tautomer, polymorph, hydrate, or solvate thereof.

The present invention also provides a method of modulating D2 receptoractivity by administering a compound of the invention or apharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof.

The present invention also provides use of a compound of the inventionor a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof, as a β-arrestin biased D2receptor agonist or antagonist. The present invention also provides useof a compound of the invention or a pharmaceutically acceptable salt,stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, as a cAMP biased agonist or antagonist. The present inventionalso provides use of a compound of the invention or a pharmaceuticallyacceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate,or solvate thereof, as a β-arrestin biased antagonist and cAMP biasedagonist.

The present invention also provides a method of treating or preventing adisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role by administering to a subject inneed thereof, a therapeutically effective amount of a selectiveβ-arrestin antagonist, or a pharmaceutically acceptable salt,stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, in combination with a pharmaceutically acceptable excipient orcarrier, such that the disease or disorder is treated or prevented.

The present invention also provides a method of treating or preventing adisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role by administering to a subject inneed thereof, a therapeutically effective amount of a compound which isa β-arrestin antagonist and a cAMP agonist, or a pharmaceuticallyacceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate,or solvate thereof, in combination with a pharmaceutically acceptableexcipient or carrier, such that the disease or disorder is treated orprevented.

The present invention also provides a method of treating or preventing adisease or disorder in which modulation of D2 receptors (e.g.,fβ-arrestin or Gi/cAMP) plays a role by administering to a subject inneed thereof, a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt, stereoisomer,racemate, tautomer, polymorph, hydrate, or solvate thereof, incombination with a pharmaceutically acceptable excipient or carrier,such that the disease or disorder is treated or prevented.

The present invention also provides a method of treating or preventing adisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role by administering to a subject inneed thereof, a therapeutically effective amount of a pharmaceuticalcomposition of the invention, such that the disease or disorder istreated or prevented.

The present invention also provides use of a selective β-arrestinantagonist, or a pharmaceutically acceptable salt, stereoisomer,racemate, tautomer, polymorph, hydrate, or solvate thereof, for treatingor preventing a disease or disorder in which modulation of D2 receptors(e.g., β-arrestin or Gi/cAMP) plays a role in a subject in need thereof.

The present invention also provides use of a compound which is aβ-arrestin antagonist and a cAMP agonist, or a pharmaceuticallyacceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate,or solvate thereof, for treating or preventing a disease or disorder inwhich modulation of D2 receptors (e.g., β-arrestin or Gi/cAMP) plays arole in a subject in need thereof.

The present invention also provides use of a compound of the invention,or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof, or use of a pharmaceuticalcomposition of the invention, for treating or preventing a disease ordisorder in which modulation of D2 receptors (e.g., β-arrestin orGi/cAMP) plays a role in a subject in need thereof.

The present invention also provides use of a selective β-arrestinantagonist, or a pharmaceutically acceptable salt, stereoisomer,racemate, tautomer, polymorph, hydrate, or solvate thereof, in themanufacture of a medicament for the treatment or prevention of a diseaseor disorder in which modulation of D2 receptors (e.g., β-arrestin orGi/cAMP) plays a role in a subject in need thereof.

The present invention also provides use of a compound which is aβ-arrestin antagonist and a cAMP agonist, or a pharmaceuticallyacceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate,or solvate thereof, in the manufacture of a medicament for the treatmentor prevention of a disease or disorder in which modulation of D2receptors (e.g., β-arrestin or Gi/cAMP) plays a role in a subject inneed thereof.

The present invention also provides use of a compound of the invention,or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof, or use of a pharmaceuticalcomposition of the invention, in the manufacture of a medicament for thetreatment or prevention of a disease or disorder in which modulation ofD2 receptors (e.g., β-arrestin or Gi/cAMP) plays a role in a subject inneed thereof.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, suitable methods and materials are described below.All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the present invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods and examples areillustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description, given by way of example, but notintended to limit the invention solely to the specific embodimentsdescribed, may be understood in conjunction with the accompanyingdrawings, in which:

FIG. 1 shows representative curves for compounds 90, 157, 158, 125, andcontrol compounds clozapine and aripiprazole across the β-arrestin andcAMP cell based assays in agonist and antagonist modes (see also Table1).

FIG. 2 shows pharmacokinetic and brain distribution of compounds 90,125, and 157 following a single intraperitoneal dose administration of30 mg/kg in male C57BL/6 mice.

FIG. 3 shows positron emission tomography at different doses of Compound90 in comparison with clozapine. Compound 90 competes with theradiotracer [¹¹C]Raclopride. Scans 1 hour after administrationdemonstrate continued high occupancy in the striatum. This matches thetime of amphetamine challenge in the behavior. Occupancies are on parwith Clozapine.

FIG. 4A shows the effect of Compound 90 in comparison with vehicle toattenuate amphetamine induced hyperactivity (AIH) over time. Compound 90dose-dependently attenuates AIH in mice and shows efficacy at 30 mg/kg.

FIG. 4B shows a bar graph representation of AIH data. “Veh.” denotesvehicle. “Cloz.” denotes clozapine.

FIG. 4C shows rotarod performance after treatment with Example 90 orClozapine. Example 90 does not induce motoric side effects at 30 mg/kgIP in mice.

FIG. 5 shows a heat map representation of binding across various GPCRreceptors for compounds of the invention (compounds 90, 157, 125, and99) and control compounds (clozapine and aripiprazole). Clozapine andother antipsychotics bind to many receptors in the brain. The inventivecompounds showed a cleaner binding profile.

FIGS. 6A to 6C show βArr2 KO mice and confirming the phenotype. One isable to replicate the decreased sensitivity to amphetamine (FIG. 6A &FIG. 6B) and apomorphine (FIG. 6C) in the βArr2 KO mice.

FIGS. 7A to 7C show Example 90 inhibiting D2R-mediated GSK3 signaling.Example 90 blocks β-arrestin signaling downstream of D2R and leads tomodulation of GSK3 signaling.

FIG. 7A shows that activation of D2R reduces GSK3-α/β (Ser 21/9)phosphorylation in HEK293T cells expressing both D2R and DISC1, and thiseffect can be blocked by 10 μM and 30 μM of Example 90, which is similarto the effect of D2R antagonist, haloperidol. FIGS. 7B and 7C show thedensitometric analysis of the intensity of phosphorylated GSK3β (Ser9)/tGSK3β (FIG. 7B), and phosphorylated GSK3α (Ser21)/t GSK3α (FIG. 7C),respectively, * p<0.05, as compared to control group, ## p<0.01, ###p<0.001 as compared to quinpirole group, n=3, One-way ANOVA.

DETAILED DESCRIPTION OF THE INVENTION Compounds of the Invention

The present invention relates to novel ligands of dopamine D2 receptors.In particular, the invention relates to a compound having Formula I:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X⁰ is C₁-C₆ alkyl, X-Cy¹, C(O)NR⁴R^(4′), NR⁴C(O)R^(4′), orCR³R^(3′)—NR⁴R^(4′), and is bonded to Z¹ or Z²;

X is C(O), CR³R^(3′), NR⁴, O, S, S(O), or S(O)₂, and is bonded to Z¹ orZ², or

-   -   Z²-Z¹—X form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁸, wherein the heterocyclyl ring,        ring G, and Cy¹ form a three-ring fused ring structure, provided        that R¹ is not optionally substituted phenyl, 2-furyl or        3-furyl, or    -   X—Z¹—R¹ form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure when n is 0 and v is 1 or 3, or    -   X—Z²—R² form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure;

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;

each R⁴ is independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R^(4′) is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl,heterocyclyl comprising one 4- to 7-membered ring and one to fourheteroatoms independently selected from N, O, and S, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and one to fourheteroatoms independently selected from N, O, and S, wherein thecycloalkyl, heterocyclyl, aryl, and heteroaryl are independentlyoptionally substituted with one or more R¹⁷;

or R⁴ and R^(4′) on the same nitrogen atom together with the nitrogenatom form a monocyclic, 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁸;

Z¹ is CR⁷, or

-   -   Z²-Z¹—X form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁸, wherein the heterocyclyl ring,        ring G, and Cy¹ form a three-ring fused ring structure, provided        that R¹ is not optionally substituted phenyl, 2-furyl or        3-furyl, or    -   X—Z¹—R¹ form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure when n is 0 and v is 1 or 3;

R⁷ is H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, or when X⁰ or X isbonded to Z¹, absent;

R¹ is H, halogen, OH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, NR²⁰R²¹,C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl,C₆-C₁₀ aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring andone to four heteroatoms independently selected from N, O, and S, C₃-C₆cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and oneto four heteroatoms independently selected from N, O, and S, providedthat when X⁰ or X forms a bond with Z¹, R¹ is not H and provided thatwhen X is bonded to Z¹ and is NR⁴, O, S, S(O), or S(O)₂, R¹ is not OH,C₁-C₆ alkoxy, NR²⁰R²¹, C₁-C₆haloalkoxy, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl; or

-   -   X—Z¹—R¹ form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure when n is 0 and v is 1 or 3, wherein the aryl, benzyl,        heteroaryl, cycloalkyl, and heterocyclyl are independently        optionally substituted with one or more substituents        independently selected from halogen, C₁-C₆ alkyl, OH, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy;

Z² is CR⁸, or

-   -   Z²-Z¹—X form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁸, wherein the heterocyclyl ring,        ring G, and Cy¹ form a three-ring fused ring structure, provided        that R¹ is not optionally substituted phenyl, 2-furyl or        3-furyl, or    -   X—Z²—R² form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure;

R⁸ is H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, or when X⁰ or X isbonded to Z², absent;

R² is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹,NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroaryl comprising one 5-or 6-membered ring and one to four heteroatoms independently selectedfrom N, O, and S, C₃-C₆ cycloalkyl, or heterocyclyl comprising one 4- to6-membered ring and one to four heteroatoms independently selected fromN, O, and S, provided that when X⁰ or X forms a bond with Z², R² is notH and provided that when X is bonded to Z² and is NR⁴, O, S, S(O), orS(O)₂, R² is not OH, C₁-C₆ alkoxy, NR²⁰R²¹, C₁-C₆ haloalkoxy,S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl; or

-   -   X—Z²—R² form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure,        wherein the aryl, benzyl, heteroaryl, cycloalkyl, and        heterocyclyl are independently optionally substituted with one        or more substituents independently selected from halogen, C₁-C₆        alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy;

each R¹⁸ is independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, or C₁-C₆ haloalkoxy; or two R¹⁸ together with the carbon atomto which they are bonded form a C(O);

q is 0, 1, or 2;

R²⁰ and R²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₆-C₁₀ aryl, wherein the aryl is optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and halogen;

Cy¹ is C₆-C₁₀ aryl, benzyl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein each ring is aromatic or partially unsaturated, orN—(C₆-C₁₀ aryl) when X is CR³R^(3′) and when X—Z¹—R¹ form a 3- to7-membered heterocyclyl ring, wherein the aryl, benzyl, and heteroarylare independently optionally substituted with one or more R¹⁶, providedthat

-   -   when p is 1, X is NH and is bonded to Z¹, and R¹ is C(O)NH₂,        then Cy¹ is not unsubstituted phenyl,    -   when p is 1, X is CH₂ and is bonded to Z¹, and R¹ is OH or        halogen, then Cy¹ is not optionally substituted phenyl,        benzoimidazolyl, benzoimidazolonyl, or        dihydroquinoxaline-2,3-dione; and    -   when p is 1, X is C(O) and is bonded to Z¹, Y is O, and R¹ is OH        or methoxy, then Cy¹ is not optionally substituted phenyl;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

Z³ is C(R⁹)₂;

each R⁹ is independently H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

p is 0 or 1;

Z′ is C(R¹²)₂; or

-   -   Z′ and Z³ together with the atom(s) to which they are bonded        form a 4- to 7-membered cycloalkyl or heterocyclyl ring which,        together with ring G, forms a fused ring structure; or    -   Z′ and Z³ together with the atom(s) to which they are bonded        form a 4- to 7-membered aryl or heteroaryl ring which, together        with ring G, forms a fused ring structure;

Z″ is C(R¹³)₂; or

-   -   Z″ and Z² together with the atom(s) to which they are bonded        form a 4- to 7-membered cycloalkyl or heterocyclyl ring which,        together with ring G, forms a fused ring structure; or    -   Z″ and Z² together with the atom(s) to which they are bonded        form a 4- to 7-membered aryl or heteroaryl ring which, together        with ring G, forms a fused ring structure;

each R¹² is independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or halogen,or two R¹² together with the carbon atom to which they are bonded form a3- to 6-membered cycloalkyl or heterocyclyl ring which, together withring G, forms a spirocyclic ring structure;

each R¹³ is independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or halogen,or two R¹³ together with the carbon atom to which they are bonded form a3- to 6-membered cycloalkyl or heterocyclyl ring which, together withring G, forms a spirocyclic ring structure; or

R¹² and R¹³, together with the carbon atoms to which they are bonded andthe nitrogen atom in ring G, form a 5- to 7-membered heterocyclyl ring,wherein the heterocyclyl ring and ring G form a bridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is

-   -   when n is 0 or 1, C(R¹⁰)₂, or    -   when n is 0, Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl or        heterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

when n is 0, Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ringoptionally substituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   when n is 0 or 1, C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   when n is 0 or 1, Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl        ring optionally substituted with one or more R¹⁹, or    -   when n is 0, Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring        optionally substituted with one or more R¹⁹, or    -   when n is 0 and Cy² is absent, pyridinonyl optionally        substituted with one or more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

Z⁵ is C(R¹¹)₂;

each R¹¹ is independently H, C₁-C₆ alkyl, C₁-C₆haloalkyl, or halogen;

n is 0 or 1;

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when n is 0 and Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷; and

provided that a compound of Formula (I) is not

1-(methylsulfonyl)-5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile;or

5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile.

In certain embodiments, the present invention relates to a compound ofFormula (I), wherein:

X⁰ is C₁-C₆ alkyl or X-Cy¹, and is bonded to Z¹ or Z²;

X is C(O), CR³R^(3′), NR⁴, O, S, S(O), or S(O)₂, and is bonded to Z¹ orZ², or

-   -   Z²-Z¹—X form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁸, wherein the heterocyclyl ring,        ring G, and Cy¹ form a three-ring fused ring structure, provided        that R¹ is not optionally substituted phenyl, 2-furyl or        3-furyl, or    -   X—Z¹—R¹ form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure when n is 0 and v is 1 or 3, or    -   X—Z²—R² form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure;

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

Z¹ is CR⁷, or

-   -   Z²-Z¹—X form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁸, wherein the heterocyclyl ring,        ring G, and Cy¹ form a three-ring fused ring structure, provided        that R¹ is not optionally substituted phenyl, 2-furyl or        3-furyl, or    -   X—Z¹—R¹ form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure when n is 0 and v is 1 or 3;

R⁷ is H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, or when X⁰ or X isbonded to Z¹, absent;

R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsselected from N, O, and S, C₃-C₆ cycloalkyl, or heterocyclyl comprisingone 4- to 6-membered ring and one to four heteroatoms selected from N,O, and S, provided that when X⁰ or X forms a bond with Z¹, R¹ is not Hand provided that when X is bonded to Z¹ and is NR⁴, O, S, S(O), orS(O)₂, R¹ is not OH, C₁-C₆ alkoxy, NR²⁰R²¹, C₁-C₆haloalkoxy,S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl; or

-   -   X—Z¹—R¹ form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure when n is 0 and v is 1 or 3,        wherein the aryl, benzyl, heteroaryl, cycloalkyl, and        heterocyclyl are optionally substituted with one or more        substituents independently selected from halogen, C₁-C₆ alkyl,        OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy;

Z² is CR⁸, or

-   -   Z²-Z¹—X form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁸, wherein the heterocyclyl ring,        ring G, and Cy¹ form a three-ring fused ring structure, provided        that R¹ is not optionally substituted phenyl, 2-furyl or        3-furyl, or    -   X—Z²—R² form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure;

R⁸ is H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, or when X⁰ or X isbonded to Z², absent;

R² is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹,NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroaryl comprising one 5-or 6-membered ring and one to four heteroatoms selected from N, O, andS, C₃-C₆ cycloalkyl, or heterocyclyl comprising one 4- to 6-memberedring and one to four heteroatoms selected from N, O, and S, providedthat when X⁰ or X forms a bond with Z², R² is not H and provided thatwhen X is bonded to Z² and is NR⁴, O, S, S(O), or S(O)₂, R² is not OH,C₁-C₆ alkoxy, NR²⁰R²¹, C₁-C₆haloalkoxy, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl; or

-   -   X—Z²—R² form a 3- to 7-membered cycloalkyl or heterocyclyl ring        optionally substituted with one or more R¹⁸, wherein the        cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the        cycloalkyl or heterocyclyl ring and Cy¹ form a fused ring        structure,        wherein the aryl, benzyl, heteroaryl, cycloalkyl, and        heterocyclyl are optionally substituted with one or more        substituents independently selected from halogen, C₁-C₆ alkyl,        OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy;

each R¹⁸ is independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, or C₁-C₆ haloalkoxy; or two R¹⁸ together with the carbon atomto which they are bonded form a C(O);

q is 0, 1, or 2;

R²⁰ and R²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₆-C₁₀ aryl, wherein the aryl is optionally substituted with one or moresubstituents selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, and halogen;

Cy¹ is C₆-C₁₀ aryl, benzyl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms selected from N, O, and Swherein each ring is aromatic or partially unsaturated, or N—(C₆-C₁₀aryl) when X is CR³R^(3′) and when X—Z¹—R¹ form a 3- to 7-memberedheterocyclyl ring, wherein the aryl, benzyl, and heteroaryl areoptionally substituted with one or more R¹⁶, provided that

-   -   when p is 1, X is NH and is bonded to Z¹, and R¹ is C(O)NH₂,        then Cy¹ is not unsubstituted phenyl,    -   when p is 1, X is CH₂ and is bonded to Z¹, and R¹ is OH or        halogen, then Cy¹ is not optionally substituted phenyl,        benzoimidazolyl, benzoimidazolonyl, or        dihydroquinoxaline-2,3-dione; and    -   when p is 1, X is C(O) and is bonded to Z¹, Y is O, and R¹ is OH        or methoxy, then Cy¹ is not optionally substituted phenyl;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

Z³ is C(R⁹)₂;

each R⁹ is independently H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

p is 0 or 1;

Z′ is C(R¹²)₂; or

-   -   Z′ and Z³ together with the atom(s) to which they are bonded        form a 4- to 7-membered cycloalkyl or heterocyclyl ring which,        together with ring G, forms a fused ring structure; or    -   Z′ and Z³ together with the atom(s) to which they are bonded        form a 4- to 7-membered aryl or heteroaryl ring which, together        with ring G, forms a fused ring structure;

Z″ is C(R¹³)₂; or

-   -   Z″ and Z² together with the atom(s) to which they are bonded        form a 4- to 7-membered cycloalkyl or heterocyclyl ring which,        together with ring G, forms a fused ring structure; or    -   Z″ and Z² together with the atom(s) to which they are bonded        form a 4- to 7-membered aryl or heteroaryl ring which, together        with ring G, forms a fused ring structure;

each R¹² is independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or halogen,or two R¹² together with the carbon atom to which they are bonded form a3- to 6-membered cycloalkyl or heterocyclyl ring which, together withring G, forms a spirocyclic ring structure;

each R¹³ is independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or halogen,or two R¹³ together with the carbon atom to which they are bonded form a3- to 6-membered cycloalkyl or heterocyclyl ring which, together withring G, forms a spirocyclic ring structure; or

R¹² and R¹³, together with the carbon atoms to which they are bonded andthe nitrogen atom in ring G, form a 5- to 7-membered heterocyclyl ring,wherein the heterocyclyl ring and ring G form a bridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is

-   -   when n is 0 or 1, C(R¹⁰)₂, or    -   when n is 0, Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl or        heterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

when n is 0, Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ringoptionally substituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   when n is 0 or 1, C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   when n is 0 or 1, Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl        ring optionally substituted with one or more R¹⁹, or    -   when n is 0, Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring        optionally substituted with one or more R¹⁹, or    -   when n is 0 and Cy² is absent, pyridinonyl optionally        substituted with one or more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

Z⁵ is C(R¹¹)₂;

each R¹¹ is independently H, C₁-C₆ alkyl, C₁-C₆haloalkyl, or halogen;

n is 0 or 1;

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms selected from N, O, and S, C₆-C₁₀ aryl,or heteroaryl comprising one or two 5- or 6-membered rings and one tofour heteroatoms selected from N, O, and S, or absent when n is 0 and Yis pyridinonyl, wherein the cycloalkyl, heterocyclyl, aryl, andheteroaryl are optionally substituted with one or more R¹⁷; and

provided that a compound of Formula (I) is not

1-(methylsulfonyl)-5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile;or

5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile.

In one embodiment, the present invention relates to a compound ofFormula (I) having Formula (II):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X⁰ is C₁-C₆ alkyl, X-Cy¹, C(O)NR⁴R^(4′), NR⁴C(O)R^(4′), orCR³R^(3′)—NR⁴R^(4′);

X is C(O), CR³R^(3′), NR⁴, O, S, S(O), or S(O)₂;

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsindependently selected from N, O, and S, C₃-C₆ cycloalkyl, orheterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, provided that whenX⁰ or X forms a bond with Z¹, R¹ is not H and provided that when X isNR⁴, O, S, S(O), or S(O)₂, R¹ is not OH, C₁-C₆ alkoxy, NR²⁰R²¹,C₁-C₆haloalkoxy, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆alkyl, wherein the aryl, benzyl, heteroaryl, cycloalkyl, andheterocyclyl are independently optionally substituted with one or moresubstituents independently selected from halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy;

q is 0, 1, or 2;

R²⁰ and R²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₆-C₁₀ aryl, wherein the aryl is optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and halogen;

Cy¹ is C₆-C₁₀ aryl, benzyl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein each ring is aromatic or partially unsaturated,wherein the aryl, benzyl, and heteroaryl are independently optionallysubstituted with one or more R¹⁶, provided that

-   -   when X is NH and R¹ is C(O)NH₂, then Cy¹ is not unsubstituted        phenyl,    -   when X is CH₂ and R¹ is OH or halogen, then Cy¹ is not        optionally substituted phenyl, benzoimidazolyl,        benzoimidazolonyl, or dihydroquinoxaline-2,3-dione; and    -   when X is C(O), Y is O, and R¹ is OH or methoxy, then Cy¹ is not        optionally substituted phenyl;    -   each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl),        S(O)_(q)—(C₁-C₃) alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl,        or NO₂;

R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen, or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   when Cy² is absent, pyridinonyl optionally substituted with one        more R¹⁷, or

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.

In certain embodiments, in Formula II, X⁰ is C₁-C₆ alkyl or X-Cy¹.

In certain embodiments, in Formula II, when X═—C(O)Et, then R¹ is not—CH₂OMe or Ph.

In certain embodiments, in Formula II, when Cy₁ taken together with thepiperidine ring forms a fused ring, then R¹ is not Ph, 2-furyl, or3-furyl.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4, or 5.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein t is 0,1, 2, 3, 4, or 5.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (II) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention relates to a compound ofFormula (I) having Formula (III):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X⁰ is C₁-C₆ alkyl or X-Cy¹;

X is C(O), CR³R^(3′), NR⁴, O, S, S(O), or S(O)₂;

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R² is halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹,NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroaryl comprising one 5-or 6-membered ring and one to four heteroatoms independently selectedfrom N, O, and S, C₃-C₆ cycloalkyl, or heterocyclyl comprising one 4- to6-membered ring and one to four heteroatoms independently selected fromN, O, and S, provided that when X is NR⁴, O, S, S(O), or S(O)₂, R² isnot OH, C₁-C₆ alkoxy, NR²⁰R²¹, C₁-C₆ haloalkoxy, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl; wherein the aryl, benzyl,heteroaryl, cycloalkyl, and heterocyclyl are independently optionallysubstituted with one or more substituents independently selected fromhalogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy;

q is 0, 1, or 2;

R²⁰ and R²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₆-C₁₀ aryl, wherein the aryl is optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and halogen;

Cy¹ is C₆-C₁₀ aryl, benzyl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein each ring is aromatic or partially unsaturated,wherein the aryl, benzyl, and heteroaryl are independently optionallysubstituted with one or more R¹⁶;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   when Cy² is absent, pyridinonyl optionally substituted with one        more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.

In certain embodiments, a compound of Formula (III) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (III) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5.

In certain embodiments, a compound of Formula (III) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5.

In certain embodiments, a compound of Formula (III) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention relates to a compound ofFormula (I) having Formula (IV):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X⁰ is C₁-C₆ alkyl or X-Cy¹;

X is C(O), CR³R^(3′), NR⁴, O, S, S(O), or S(O)₂;

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R² is halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsindependently selected from N, O, and S, C₃-C₆ cycloalkyl, orheterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, provided that whenX is NR⁴, O, S, S(O), or S(O)₂, R² is not OH, C₁-C₆ alkoxy, NR²⁰R²¹,C₁-C₆ haloalkoxy, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆alkyl, wherein the aryl, benzyl, heteroaryl, cycloalkyl, andheterocyclyl are independently optionally substituted with one or moresubstituents independently selected from halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy;

q is 0, 1, or 2;

R²⁰ and R²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₆-C₁₀ aryl, wherein the aryl is optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and halogen;

Cy¹ is C₆-C₁₀ aryl, benzyl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein each ring is aromatic or partially unsaturated,wherein the aryl, benzyl, and heteroaryl are independently optionallysubstituted with one or more R¹⁶;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   when Cy² is absent, pyridinonyl optionally substituted with one        more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.

In certain embodiments, a compound of Formula (IV) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (IV) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5.

In certain embodiments, a compound of Formula (IV) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5.

In certain embodiments, a compound of Formula (IV) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4, or 5.

In certain embodiments, a compound of Formula (IV) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (IV) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein t is 0,1, 2, 3, 4, or 5.

In another embodiment, the present invention relates to a compound ofFormula (I) having Formula (V):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X is CR³ or N;

R³ is H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, or C₁-C₆haloalkoxy;

each K is independently NR²², C(O), O, or CR²²R²³;

each R²² and R²³ is independently H, OH, C₁-C₆ alkyl, or C₆-C₁₀ aryl,wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, and C₁-C₆ haloalkoxy;

Cy¹ is C₆-C₁₀ aryl, benzyl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein each ring is aromatic or partially unsaturated,wherein the aryl, benzyl, and heteroaryl are independently optionallysubstituted with one or more R¹⁶;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

q is 0, 1, or 2;

w is 1, 2, 3, or 4;

p is 0 or 1;

R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   when Cy² is absent, pyridinonyl optionally substituted with one        or more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷; and

provided that a compound of Formula (V) is not

1-(methylsulfonyl)-5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile;or

5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile.

In certain embodiments, in Formula (V), Cy² is not benzopyridyl.

In another embodiment, a compound of Formula (V) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In another embodiment, a compound of Formula (V) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein g is 0,1, 2, 3, 4, or 5.

In another embodiment, a compound of Formula (V) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein w is 1or 2.

In another embodiment, a compound of Formula (V) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein w is 1or 2; and g is 0, 1, 2, 3, 4, or 5.

In another embodiment, the present invention relates to a compound ofFormula (I) having Formula (VI):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X is CR³ or N;

R³ is H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, or C₁-C₆haloalkoxy;

each K is independently NR²², C(O), O, or CR²²R²³;

each R₂₂ and R₂₃ is independently H, OH, C₁-C₆ alkyl, or C₆-C₁₀ aryl,wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, and C₁-C₆ haloalkoxy;

Cy¹ is C₆-C₁₀ aryl, benzyl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein each ring is aromatic or partially unsaturated,wherein the aryl, benzyl, and heteroaryl are independently optionallysubstituted with one or more R¹⁶;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

q is 0, 1, or 2;

w is 1, 2, 3, or 4;

p is 0 or 1;

R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   when Cy² is absent, pyridinonyl optionally substituted with one        or more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.

In another embodiment, the present invention relates to a compound ofFormula (I) having Formula (VII):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X is CR³R^(3′), NR⁴, or O;

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

q is 0, 1, or 2;

h is 1, 2, or 3;

g is 0, 1, 2, 3, or 4;

p is 0 or 1;

each R²⁴ and R²⁵ are independently H, C₁-C₃ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy, or R²⁴ and R²⁵ together with thecarbon atom to which they are bonded form C(O);

R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   when Cy² is absent, pyridinonyl optionally substituted with one        or more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.

In certain embodiments, a compound of Formula (VII) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to a compound ofFormula (I) having Formula (VIII):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X is CR³R^(3′), NR⁴, or O;

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

q is 0, 1, or 2;

h is 1, 2, or 3;

g is 0, 1, 2, 3, or 4;

p is 0 or 1;

each R²⁴ and R²⁵ are independently H, C₁-C₃ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy, or R²⁴ and R²⁵ together with thecarbon atom to which they are bonded form C(O);

R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or when Cy² is absent,        pyridinonyl optionally substituted with one or more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.

In another embodiment, the present invention relates to a compound ofFormula (I) having Formula (IX):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X is CR³R^(3′), NR⁴, or O;

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆haloalkoxy;

R² is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆haloalkoxy, provided that when X is NR⁴ or O, R² is not OH, C₁-C₆alkoxy, or C₁-C₆haloalkoxy;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

q is 0, 1, or 2;

i is 0, 1, or 2;

g is 0, 1, 2, 3, or 4;

p is 0 or 1;

R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or when Cy² is absent,        pyridinonyl optionally substituted with one or more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.

In another embodiment, the present invention relates to a compound ofFormula (I) having Formula (X):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

X is CR³R^(3′), NR⁴, or O;

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆haloalkoxy, provided that when X is NR⁴ or O, R¹ is not OH, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy;

R² is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆haloalkoxy;

each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;

q is 0, 1, or 2;

i is 0, 1, or 2;

g is 0, 1, 2, 3, or 4;

p is 0 or 1;

R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or when Cy² is absent,        pyridinonyl optionally substituted with one or more R¹⁷;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.

In one embodiment, the present invention relates to a compound of theformula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R^(4′) is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl,heterocyclyl comprising one 4- to 7-membered ring and one to fourheteroatoms independently selected from N, O, and S, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and one to fourheteroatoms independently selected from N, O, and S, wherein thecycloalkyl, heterocyclyl, aryl, and heteroaryl are independentlyoptionally substituted with one or more R¹⁷;

or R⁴ and R^(4′) on the same nitrogen atom together with the nitrogenatom form a monocyclic, 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁸;

R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsindependently selected from N, O, and S, C₃-C₆ cycloalkyl, orheterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, wherein the aryl,benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independentlyoptionally substituted with one or more substituents independentlyselected from halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,and C₁-C₆haloalkoxy;

each q is independently 0, 1, or 2;

R²⁰ and R²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₆-C₁₀ aryl, wherein the aryl is optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and halogen;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl areindependently optionally substituted with one or more R¹⁷;

each R³⁰ is independently halogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; and

r is 0, 1, 2, 3, or 4.

In certain embodiments, a compound of Formula (XI) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (XI) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein u is 0,1, 2, 3, or 4.

In certain embodiments, a compound of Formula (XI) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein u is 0,1, 2, 3, or 4.

In certain embodiments, a compound of Formula (XII) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (XII) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein u is 0,1, 2, 3, or 4.

In certain embodiments, a compound of Formula (XII) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein u is 0,1, 2, 3, or 4.

In one embodiment, the present invention relates to a compound of theformula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein:

R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;

R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

R^(4′) is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl,heterocyclyl comprising one 4- to 7-membered ring and one to fourheteroatoms independently selected from N, O, and S, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and one to fourheteroatoms independently selected from N, O, and S, wherein thecycloalkyl, heterocyclyl, aryl, and heteroaryl are independentlyoptionally substituted with one or more R¹⁷;

or R⁴ and R^(4′) on the same nitrogen atom together with the nitrogenatom form a monocyclic, 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁸;

R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsindependently selected from N, O, and S, C₃-C₆ cycloalkyl, orheterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, wherein the aryl,benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independentlyoptionally substituted with one or more substituents independentlyselected from halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,and C₁-C₆haloalkoxy;

each q is independently 0, 1, or 2;

R²⁰ and R²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₆-C₁₀ aryl, wherein the aryl is optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and halogen;

Z⁶ is C(R¹⁴)₂;

v is 1, 2, or 3;

each R¹⁴ is independently H or C₁-C₃ alkyl;

Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁹;

each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl,NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or

two R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or

Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹;

each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, or halogen;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O);

Y is

-   -   C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or    -   Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹, or    -   Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionally        substituted with one or more R¹⁹;

R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;

R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;

Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl areindependently optionally substituted with one or more R¹⁷;

each R³⁰ is independently halogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; and

r is 0, 1, 2, 3, or 4.

In certain embodiments, a compound of Formula (XIII) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (XIII) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (XIII) is of the formula:

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein t is 0,1, 2, 3, or 4.

In one embodiment, X⁰ is C₁-C₆ alkyl or X-Cy¹. In another embodiment, X⁰is C₁-C₃ alkyl or X-Cy¹. In yet another embodiment, X⁰ is C₁-C₃ alkyl.In another embodiment, X⁰ is X-Cy¹. In one embodiment, X⁰ is bonded toZ¹. In another embodiment, X⁰ is bonded to Z². In certain embodiments,X⁰ is C₁-C₆ alkyl, and R¹ is OH. In certain embodiments, X⁰ is Me, andR¹ is OH.

In one embodiment, X is CR³R^(3′), NR⁴, or O. In another embodiment, Xis CR³R^(3′). In another embodiment, X is NR⁴. In yet anotherembodiment, X is O. In another embodiment, X is CR³. In anotherembodiment, X is C(O). In a further embodiment, X is O, N(CH₃), CH(OH),C(O), or CH₂

In one embodiment, Y is C(O), CR⁵R^(5′), NR⁶, or O. In anotherembodiment, Y is CR⁵R^(5′). In another embodiment, Y is NR⁶. In yetanother embodiment, Y is O. In another embodiment, Y is CR⁵. In anotheryet embodiment, Y is C(O). In a further embodiment, Y is O, C(O), NH,C(CH₃)OH, or CH₂. In yet another embodiment, Y—Z⁴—R¹⁷ form a 4- to7-membered heterocyclyl ring optionally substituted with one or more R¹⁹when n is 0. In another embodiment, Y—Z⁴-Z⁶ form a 4- to 7-memberedheterocyclyl ring optionally substituted with one or more R¹⁹.

In one embodiment, Z¹ is C. In another embodiment, Z¹ is CR₇. In anotherembodiment, Z¹ is CH.

In one embodiment, Z² is C. In another embodiment, Z² is CR₈. In anotherembodiment, Z² is CH.

In one embodiment, Z′ is C(R¹²)₂. In another embodiment, Z′ and Z³together with the atom(s) to which they are bonded form a 4- to7-membered cycloalkyl or heterocyclyl ring which, together with ring G,forms a fused ring structure. In yet another embodiment, Z′ and Z³together with the atom(s) to which they are bonded form a 4- to7-membered aryl or heteroaryl ring which, together with ring G, forms afused ring structure.

In one embodiment, Z″ is C(R¹³)₂. In another embodiment, Z″ and Z²together with the atom(s) to which they are bonded form a 4- to7-membered cycloalkyl or heterocyclyl ring which, together with ring G,forms a fused ring structure. In yet another embodiment, Z″ and Z²together with the atom(s) to which they are bonded form a 4- to7-membered aryl or heteroaryl ring which, together with ring G, forms afused ring structure.

In one embodiment, R¹ is H, C₁-C₆ alkyl, halogen, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, NR²⁰R²¹ or benzyl. In anotherembodiment, R¹ is H, C₁-C₆ alkyl, halogen, or OH. In yet anotherembodiment, R¹ is H, methyl, isopropyl, F, OH or benzyl. In anotherembodiment, R¹ is H, methyl, F, or OH. In certain embodiments, R¹ is H.In certain embodiments, R¹ is C₁-C₆ alkyl. In certain embodiments, R¹ isMe. In certain embodiments, R¹ is isopropyl. In certain embodiments, R¹is C₁-C₆ hydroxyalkyl. In certain embodiments, R¹ is —CH₂OH. In certainembodiments, R¹ is C₂-C₆ alkenyl (e.g., vinyl). In certain embodiments,R¹ is C₂-C₆ alkynyl (e.g., —C≡CH). In certain embodiments, R¹ is halogen(e.g., F). In certain embodiments, R¹ is C₁-C₆ alkoxy (e.g., OMe). Inanother embodiment, when X is bonded to Z¹ and is NR⁴, O, S, S(O), orS(O)₂, R¹ is not OH, C₁-C₆ alkoxy, NR²⁰R²¹, C₁-C₆haloalkoxy,S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl.

In one embodiment, when X⁰ or X forms a bond with Z¹, R¹ is not H. Inanother embodiment, when X⁰ or X forms a bond with Z¹, R¹ is C₁-C₆alkyl, halogen, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy,NR²⁰R²¹ or benzyl. In another embodiment, when X⁰ or X forms a bond withZ¹, R¹ is OH or C₁-C₆ alkoxy. In certain embodiments, R¹ is as describedherein, provided that R¹ is not OH. In certain embodiments, when X⁰ is—CH₂-Cy¹ or —C(O)-Cy¹, R¹ is not OH. In certain embodiments, when X⁰ is—CH₂-phenyl or —C(O)-phenyl, wherein the phenyl is optionallysubstituted with one or more R¹⁶, then R¹ is not OH. In certainembodiments, R¹ is as described herein, provided that R¹ is not C₁-C₆alkoxy (e.g., —OMe). In certain embodiments, when X⁰ is C(O)-phenyl,wherein the phenyl is optionally substituted with one or more R¹⁶, thenR¹ is not C₁-C₆ alkoxy (e.g., —OMe). In certain embodiments, R¹ is asdescribed herein, provided that R¹ is not C(O)NR²⁰R²¹ (e.g., C(O)NH₂).

In one embodiment, R² is H, C₁-C₆ alkyl, halogen, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, NR²⁰R²¹ or benzyl. In anotherembodiment, R² is H, C₁-C₆ alkyl, halogen, or OH. In yet anotherembodiment, R² is H, methyl, F, or OH. In another embodiment, when X⁰ orX forms a bond with Z², R² is not H. In another embodiment, when X⁰ or Xforms a bond with Z², R² is C₁-C₆ alkyl, halogen, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, NR²⁰R²¹ or benzyl. In yet anotherembodiment, when X⁰ or X forms a bond with Z², R² is OH or C₁-C₆ alkoxy.In one embodiment, R² is H. In one embodiment, R² is C₁-C₆ alkyl. In oneembodiment, R² is Me. In one embodiment, R² is halogen. In oneembodiment, R² is F. In one embodiment, R² is OH.

In another embodiment, when X is bonded to Z² and is NR⁴, O, S, S(O), orS(O)₂, R² is not OH, C₁-C₆ alkoxy, NR²⁰R²¹, C₁-C₆ haloalkoxy,S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl.

In one embodiment, R³ is H or (C₁-C₆) alkyl. In another embodiment, R³is H or (C₁-C₃) alkyl. In yet another embodiment, R³ is H, methyl,ethyl, propyl, or iso-propyl.

In one embodiment, R^(3′) is H or (C₁-C₆) alkyl. In another embodiment,R^(3′) is H or (C₁-C₃) alkyl. In yet another embodiment, R^(3′) is H,methyl, ethyl, propyl, or iso-propyl.

In one embodiment, at least one instance of R⁴ is H or (C₁-C₆) alkyl. Inanother embodiment, at least one instance of R⁴ is H or (C₁-C₃) alkyl.In another embodiment, at least one instance of R⁴ is H, methyl, ethyl,propyl, or iso-propyl. In certain embodiments, at least one instance ofR⁴ is H. In certain embodiments, each R⁴ is H. In certain embodiments,at least one instance of R⁴ is (C₁-C₆) alkyl (e.g., Me). In certainembodiments, all instances of R⁴ are the same.

In certain embodiments, R^(4′) is H. In certain embodiments, R^(4′) isC₁-C₆ alkyl (e.g., Me). In certain embodiments, R^(4′) is C₁-C₆haloalkyl (e.g., —CF₃). In certain embodiments, R^(4′) is C₃-C₈cycloalkyl optionally substituted with one or more R¹⁷. In certainembodiments, R^(4′) is cyclopropyl. In certain embodiments, R^(4′) isheterocyclyl comprising one 4- to 7-membered ring and one to fourheteroatoms independently selected from N, O, and S, wherein theheterocyclyl is optionally substituted with one or more R¹⁷. In certainembodiments, R^(4′) is C₆-C₁₀ aryl (e.g., phenyl) optionally substitutedwith one or more R¹⁷. In certain embodiments, R^(4′) is Ph. In certainembodiments, R^(4′) is heteroaryl comprising one 5- or 6-membered ringand one to four heteroatoms independently selected from N, O, and S,wherein the heteroaryl is optionally substituted with one or more R¹⁷.In certain embodiments, R^(4′) is heteroaryl comprising two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein the heteroaryl is optionally substituted with oneor more R¹⁷.

In certain embodiments, R⁴ and R^(4′) on the same nitrogen atom togetherwith the nitrogen atom form a monocyclic, 4- to 7-membered heterocyclylring (e.g., a pyrrolidinyl ring) optionally substituted with one or moreR¹⁸. In certain embodiments, R⁴ and R^(4′) on the same nitrogen atomtogether with the nitrogen atom form a pyrrolidinyl ring.

Each of R⁴ and R^(4′) is not benzyl or benzhydryl.

In one embodiment, R⁵ is H, halogen, (C₁-C₆) alkyl, or OH. In anotherembodiment, R⁵ is H, (C₁-C₃) alkyl, or OH. In yet another embodiment, R⁵is H, methyl, ethyl, propyl, iso-propyl, or OH.

In one embodiment, R^(5′) is H, (C₁-C₆) alkyl, or OH. In anotherembodiment, R^(5′) is H, (C₁-C₃) alkyl, or OH. In yet anotherembodiment, R^(5′) is H, methyl, ethyl, propyl, iso-propyl, or OH.

In one embodiment, R⁶ is H or (C₁-C₆) alkyl. In another embodiment, R⁶is H or (C₁-C₃).

In yet another embodiment, R⁶ is H, methyl, ethyl, propyl or iso-propyl.

In one embodiment, R⁷ is H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Inanother embodiment, R⁷ is H, or C₁-C₃ alkyl. In yet another embodiment,R⁷ is H, methyl, ethyl, propyl, or isopropyl. In another embodiment, R⁷is absent. In another embodiment, R⁷ is absent when X⁰ or X forms a bondwith Z¹.

In one embodiment, R⁸ is H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Inanother embodiment, R⁸ is H, or C₁-C₃ alkyl. In yet another embodiment,R⁸ is H, methyl, ethyl, propyl, or isopropyl. In another embodiment, R⁸is absent. In another embodiment, R⁸ is absent when X⁰ or X forms a bondwith Z².

In one embodiment, R⁹ is H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. Inanother embodiment, R⁹ is H or C₁-C₆ alkyl. In yet another embodiment,R⁹ is H or C₁-C₃ alkyl. In further embodiment, R⁹ is H, methyl, ethyl,propyl, or isopropyl. In a preferred embodiment, R⁹ is H.

In one embodiment, R¹⁰ is H or C₁-C₆ alkyl. In another embodiment, R¹⁰is H or C₁-C₃ alkyl. In yet another embodiment, R¹⁰ is H, methyl, ethyl,propyl, or isopropyl. In a preferred embodiment, R¹⁰ is H.

In one embodiment, R¹¹ is H or C₁-C₆ alkyl. In another embodiment, R¹¹is H or C₁-C₃ alkyl. In yet another embodiment, R¹¹ is H, methyl, ethyl,propyl, or isopropyl. In a preferred embodiment, R¹¹ is H.

In one embodiment, R¹² is H or C₁-C₃ alkyl. In another embodiment, R¹²is H, methyl, ethyl, propyl, or isopropyl. In a preferred embodiment,R¹² is H or methyl. In another embodiment, two R¹² together with thecarbon atom to which they are bonded form a 3- to 6-membered cycloalkylor heterocyclyl ring which, together with ring G, forms a spirocyclicring structure.

In one embodiment, R¹³ is H or C₁-C₃ alkyl. In another embodiment, R¹³is H, methyl, ethyl, propyl, or isopropyl. In a preferred embodiment,R¹³ is H or methyl. In another embodiment, two R¹³ together with thecarbon atom to which they are bonded form a 3- to 6-membered cycloalkylor heterocyclyl spirocyclic ring which, together with ring G, forms aspirocyclic ring structure.

In another embodiment, R¹² and R¹³, together with the carbon atoms towhich they are bonded and the nitrogen atom in ring G, form a 5- to7-membered heterocyclyl ring, wherein the heterocyclyl ring and ring Gform a bridged ring structure.

In one embodiment, R¹⁴ is H or C₁-C₃ alkyl. In another embodiment, R¹⁴is H, methyl, ethyl, propyl, or isopropyl. In a preferred embodiment,R¹⁴ is H or methyl.

In one embodiment, each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C(O)—(C₁-C₃ alkyl),S(O)_(q)—(C₁-C₃ alkyl), NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂.In another embodiment, each R¹⁶ is independently halogen, C₁-C₂ alkyl,OH, C₁-C₂ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C(O)(C₁-C₃) alkyl,S(O)_(q)(C₁-C₂) alkyl, NH₂, N(C₁-C₂ alkyl)₂, CN, (C₆-C₁₀) aryl, or NO₂.In yet another embodiment, each R¹⁶ is independently F, C₁, methyl,ethyl, OCH₃, OCF₃, CF₃, NH₂, N(CH₃)₂, NO₂, S(O)₂CH₃, C(O)CH₃, or CN.

In one embodiment, each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂. Inanother embodiment, each R¹⁷ is independently halogen, halogen, C₁-C₂alkyl, OH, C₁-C₂ alkoxy, C₁-C₂ haloalkyl, C₁-C₂haloalkoxy, C(O)—C₁-C₃alkyl, S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₂ alkyl)₂, CN, C₆-C₁₀ aryl, orNO₂. In yet another embodiment, each R¹⁷ is independently F, C₁, methyl,ethyl, OCH₃, OCF₃, CF₃, NH₂, N(CH₃)₂, NO₂, S(O)₂CH₃, C(O)CH₃, CN orphenyl. In another embodiment, Y—Z⁴—R¹⁷ form a 4- to 7-memberedheterocyclyl ring optionally substituted with one or more R¹⁹. Inanother embodiment, two R¹⁷ together with the carbon atoms to which theyare bonded form a C₆-C₁₀ aryl or heteroaryl optionally substituted withone or more R¹⁹.

In one embodiment, each R¹⁸ is independently halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In another embodiment,each R¹⁸ is independently C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, orC₁-C₃ haloalkoxy. In yet another embodiment, each R¹⁸ is independentlymethyl, OCH₃, OCH₂CH₃, OCF₃, CF₃, CHF₂, or CH₂CF₃. In anotherembodiment, two R¹⁸ together with the carbon atom to which they arebonded form a C(O).

In one embodiment, each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, or C₁-C₆haloalkoxy. In another embodiment, each R¹⁹ isindependently C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkyl, or C₁-C₃haloalkoxy. In yet another embodiment, each R¹⁹ is independently methyl,OCH₃, OCH₂CH₃, OCF₃, CF₃, CHF₂, or CH₂CF₃.

In one embodiment, R²⁰ is H, C₁-C₆ alkyl, or unsubstituted C₆-C₁₀ aryl.In another embodiment, R²⁰ is H, C₁-C₃ alkyl, or unsubstituted C₆ aryl.In yet another embodiment, R²⁰ is H, methyl, ethyl, propyl, isopropyl,or phenyl.

In one embodiment, R²¹ is H, C₁-C₆ alkyl, or unsubstituted C₆-C₁₀ aryl.In another embodiment, R²¹ is H, C₁-C₄ alkyl, or unsubstituted C₆ aryl.In yet another embodiment, R²¹ is H, methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, tert-butyl, or phenyl.

In one embodiment, R²² is H, OH, C₁-C₆ alkyl, or C₆-C₁₀ aryl, whereinthe aryl is optionally substituted with one or more substituentsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, or C₁-C₆haloalkoxy. In another embodiment, R²² is H, C₁-C₃alkyl, or C₆-C₁₀ aryl, wherein the aryl is optionally substituted withone or more substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In yetanother embodiment, R²² is H, methyl, ethyl, propyl, isopropyl or phenyloptionally substituted with halogen.

In one embodiment, R²³ is H, OH, C₁-C₆ alkyl, or C₆-C₁₀ aryl, whereinthe aryl is optionally substituted with one or more substituentsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, or C₁-C₆ haloalkoxy. In another embodiment, R²³ is H,C₁-C₃alkyl, or C₆-C₁₀ aryl, wherein the aryl is optionally substitutedwith one or more substituents independently selected from halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In yetanother embodiment, R²³ is H, OH, methyl, ethyl, propyl, isopropyl orphenyl optionally substituted with halogen.

In one embodiment, each R²⁴ is independently H, C₁-C₃ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In another embodiment,each R²⁴ is independently H, C₁-C₃ alkyl, OH, C₁-C₃ alkoxy, C₁-C₃haloalkyl, or C₁-C₃ haloalkoxy. In yet embodiment, each R²⁴ isindependently H, C₁-C₃ alkyl, OH, or C₁-C₃ alkoxy.

In one embodiment, each R²⁵ is independently H, C₁-C₃ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In another embodiment,each R²⁵ is independently H, C₁-C₃ alkyl, OH, C₁-C₃ alkoxy, C₁-C₃haloalkyl, or C₁-C₃ haloalkoxy. In yet embodiment, each R²⁵ isindependently H, C₁-C₃ alkyl, OH, or C₁-C₃ alkoxy.

In another embodiment, R²⁴ and R²⁵ together with the carbon atom towhich they are bonded form C(O).

In one embodiment, K is NR²². In another embodiment, K is O. In yetanother embodiment, K is CR²²R²³. In certain embodiments, K is asdescribed herein, provided that no instance of K is C(O).

In one embodiment, Cy¹ is C₆-C₁₀ aryl optionally substituted with one ormore R¹⁶. In another embodiment, Cy¹ is benzyl optionally substitutedwith one or more R¹⁶. In yet another embodiment, Cy¹ is heteroarylcomprising one or two 5- or 6-membered rings and one to four heteroatomsindependently selected from N, O, or S optionally substituted one ormore R¹⁶. In another embodiment, Cy¹ is N—(C₆-C₁₀ aryl) when X isCR³R^(3′) and when X—Z¹—R¹ form a 3- to 7-membered heterocyclyl ringoptionally substituted one or more R¹⁶. In another embodiment, Cy¹ isphenyl, pyridinyl, pyrazinyl, or benzothiazole, wherein the phenyl,pyridinyl, pyrazinyl, and benzothiazole are independently optionallysubstituted with one or more R¹⁶

In one embodiment, when p is 1, X is NH and is bonded to Z¹, and R¹ isC(O)NH₂, Cy¹ is not unsubstituted phenyl. In another embodiment, when pis 1, X is CH₂ and is bonded to Z¹, and R¹ is OH or halogen, then Cy¹ isnot phenyl, benzoimidazolyl, benzoimidazolonyl, ordihydroquinoxaline-2,3-dione. In another embodiment, when p is 1, X isC(O) and is bonded to Z¹, Y is O, and R¹ is OH or methoxy, then Cy¹ isnot optionally substituted phenyl.

In one embodiment, Cy² is C₃-C₈ cycloalkyl optionally substituted one ormore R¹⁷. In another embodiment, Cy² is heterocyclyl comprising one 4-to 7-membered ring and one to four heteroatoms independently selectedfrom N, O, or S optionally substituted one or more R¹⁷. In yet anotherembodiment, Cy² is C₆-C₁₀ aryl optionally substituted one or more R¹⁷.In another embodiment, Cy² is heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, or S optionally substituted one or more R¹⁷. In anotherembodiment, Cy² is absent when n is 0 and Y is pyridinonyl.

In one embodiment, X—Z²-Z¹ form a 4- to 7-membered heterocyclyl ringoptionally substituted with one or more R¹⁸, wherein the heterocyclylring, ring G, and Cy¹ form a three-ring fused ring structure.

In one embodiment, X—Z¹—R¹ form a 3- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁸, whereinthe cycloalkyl or heterocyclyl ring is bonded to Cy¹. In anotherembodiment, X—Z¹—R¹ form a 3- to 7-membered cycloalkyl or heterocyclylring optionally substituted with one or more R¹⁸, wherein the cycloalkylor heterocyclyl ring and Cy¹ form a fused ring structure when n is 0 andv is 0 or 1.

In one embodiment, X—Z²—R² form a 3- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁸, whereinthe cycloalkyl or heterocyclyl ring is bonded to Cy¹. In anotherembodiment, X—Z²—R² form a 3- to 7-membered cycloalkyl or heterocyclylring optionally substituted with one or more R¹⁸, wherein the cycloalkylor heterocyclyl ring and Cy¹ form a fused ring structure.

In one embodiment, Z²-Z¹—X form a 4- to 7-membered heterocyclyl ringoptionally substituted with one or more R¹⁸, wherein the heterocyclylring, ring G, and Cy¹ form a three-ring fused ring structure. In anotherembodiment, when Z²-Z¹—X form a 4- to 7-membered heterocyclyl ringoptionally substituted with one or more R¹⁸, wherein the heterocyclylring, ring G, and Cy¹ form a three-ring fused ring structure, R¹ is notoptionally substituted phenyl, 2-furyl or 3-furyl.

In one embodiment, q is 0. In another embodiment, q is 1. In yet anotherembodiment, q is 2.

In one embodiment, v is 1. In another embodiment, v is 2. In yet anotherembodiment, v is 3.

In one embodiment, n is 0. In another embodiment, n is 1.

In one embodiment, p is 0. In another embodiment, p is 1.

In one embodiment, w is 1, 2, 3, or 4. In another embodiment, w is 1. Inyet another embodiment, w is 2. In another embodiment, w is 3.

In one embodiment, h is 1, 2, or 3. In another embodiment, h is 1 or 2.In a preferred embodiment, h is 1.

In one embodiment, g is 0. In one embodiment, g is 1. In anotherembodiment, g is 2. In yet another embodiment, g is 3. In anotherembodiment, g is 4. In a preferred embodiment, g is 1 or 2.

In one embodiment, i is 0. In another embodiment, i is 1. In yet anotherembodiment, i is 2.

In certain embodiments, t is 0, In certain embodiments, t is 1. Incertain embodiments, t is 2, 3, 4. In certain embodiments, t is 5.

In certain embodiments, u is 0. In certain embodiments, u is 1. Incertain embodiments, u is 2 or 3. In certain embodiments, u is 4.

In one embodiment, Cy¹ is not

when p is 1 and X is bound to Z¹.

In another embodiment Cy² is not

when p is 1 and X is bound to Z¹.

In another embodiment, Cy¹ and Cy² are

optionally substituted with one or more preferred substituents.

In one embodiment, X⁰ is X-Cy¹ and X is bonded to Z¹. In anotherembodiment, X⁰ is X-Cy¹, X is bonded to Z¹ and R¹ is methyl. In yetanother embodiment, X⁰ is X-Cy¹, X is bonded to Z¹, R¹ is methyl and R⁹is H. In another embodiment, X⁰ is X-Cy¹, X is bonded to Z¹, R¹ ismethyl, R⁹ is H, and R¹² is H. In another embodiment, X⁰ is X-Cy¹, X isbonded to Z¹, R¹ is methyl, R⁹ is H, R¹² is H, and R¹³ is H.

In one embodiment, X⁰ is X-Cy¹ and X is bonded to Z¹. In anotherembodiment, X⁰ is X-Cy¹, X is bonded to Z¹ and R² is methyl. In yetanother embodiment, X⁰ is X-Cy¹, X is bonded to Z¹, R² is methyl and R⁹is H. In another embodiment, X⁰ is X-Cy¹, X is bonded to Z¹, R² ismethyl, R⁹ is H, and R¹² is H. In another embodiment, X⁰ is X-Cy¹, X isbonded to Z¹, R² is methyl, R⁹ is H, R¹² is H, and R¹³ is H.

In one embodiment, X⁰ is X—Cy¹ and, X is bonded to Z¹, R¹ is methyl andX is NR⁴. In another embodiment, X⁰ is X-Cy¹, X is bonded to Z¹, R¹ ismethyl and X is CR³R^(3′). In yet another embodiment, X⁰ is X-Cy¹, X isbonded to Z¹, R¹ is methyl and X is C(O). In another embodiment, X⁰ isX-Cy¹, X is bonded to Z¹, R¹ is methyl and X is O.

In one embodiment, X⁰ is X-Cy¹, X is bonded to Z², R² is methyl and X isNR⁴. In another embodiment, X⁰ is X-Cy¹, X is bonded to Z², R² is methyland X is CR³R^(3′). In yet another embodiment, X⁰ is X-Cy¹, X is bondedto Z², R² is methyl and X is C(O). In another embodiment, X⁰ is X-Cy¹, Xis bonded to Z¹, R² is methyl and X is O.

In certain embodiments, X⁰ is C(O)NR⁴R^(4′). In certain embodiments, X⁰is C(O)NHR^(4′) (e.g., C(O)NH(C₁-C₆ alkyl)). In certain embodiments, X⁰is C(O)NHMe. In certain embodiments, X⁰ is C(O)N(C₁-C₆ alkyl)₂. Incertain embodiments, X⁰ is C(O)N(Me)₂. In certain embodiments, X⁰ isC(O)NHR^(4′), wherein R^(4′) is C₃-C₈ cycloalkyl (e.g., cyclopropyl)optionally substituted with one or more R¹⁷. In certain embodiments, X⁰is C(O)NH(cyclopropyl). In certain embodiments, X⁰ is C(O)NHR^(4′),wherein R^(4′) is phenyl optionally substituted with one or more R¹⁷. Incertain embodiments, X⁰ is C(O)NHPh. In certain embodiments, X⁰ isC(O)NR⁴R^(4′), wherein R⁴ and R^(4′) together with the nitrogen atom towhich R⁴ and R^(4′) are bound form a monocyclic, 4- to 7-memberedheterocyclyl ring (e.g., a pyrrolidinyl ring) optionally substitutedwith one or more R¹⁸. In certain embodiments, X⁰ is

In certain embodiments, X⁰ is NR⁴C(O)R^(4′). In certain embodiments, X⁰is NHC(O)R^(4′). In certain embodiments, X⁰ is NHC(O)(C₁-C₆ alkyl). Incertain embodiments, X⁰ is NHC(O)Me. In certain embodiments, X⁰ isNHC(O)(C₁-C₆ haloalkyl). In certain embodiments, X⁰ is NHC(O)CF₃. Incertain embodiments, X⁰ is N(C₁-C₆ alkyl)C(O)R^(4′). In certainembodiments, X⁰ is NMeC(O)R^(4′) (e.g., NMeC(O)Me). In certainembodiments, X⁰ is NHC(O)R^(4′), wherein R^(4′) is C₃-C₈ cycloalkyloptionally substituted with one or more R¹⁷. In certain embodiments, X⁰is NHC(O)(cyclopropyl).

In certain embodiments, X⁰ is CR³R^(3′)—NR⁴R^(4′). In certainembodiments, X⁰ is CH₂—NR⁴R^(4′.) In certain embodiments, X⁰ isCH₂—NHR^(4′). In certain embodiments, X⁰ is CH₂—NH(C₁-C₆alkyl) (e.g.,CH₂—NHMe).

In certain embodiments, at least one instance of R³⁰ is halogen. Incertain embodiments, at least one instance of R³⁰ is F. In certainembodiments, at least one instance of R³⁰ is C₁, Br, or I. In certainembodiments, at least one instance of R³⁰ is C₁₋₆ alkyl. In certainembodiments, at least one instance of R³⁰ is Me. In certain embodiments,at least one instance of R³⁰ is Et, Pr, or Bu. In certain embodiments,at least one instance of R³⁰ is C₁₋₆ haloalkyl. In certain embodiments,at least one instance of R³⁰ is —CF₃. In certain embodiments, r is 0. Incertain embodiments, r is 1, 2, or 3. In certain embodiments, r is 4.

In one embodiment, the compound of Formula (I) or (V) is not1-(methylsulfonyl)-5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile.In another embodiment, the compound of Formula (I) or (V) is not5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile.

In one embodiment, when X is NH and R¹ is C(O)NH₂, Cy¹ is notunsubstituted phenyl.

In another embodiment, when X is CH₂ and R¹ is OH or halogen, then Cy¹is not optionally substituted phenyl, benzoimidazolyl,benzoimidazolonyl, or dihydroquinoxaline-2,3-dione.

Non-limiting illustrative compounds of the invention include:

-   3-(4-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(2-methoxyphenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(3-methoxyphenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(4-methoxyphenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(3-fluorophenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(4-fluorophenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(2,4-difluorophenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(2,5-difluorophenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(3-chlorophenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(4-chlorophenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(2-(3,4-dichlorophenoxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(2-(o-tolyloxy)ethyl)pyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(2-(m-tolyloxy)ethyl)pyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(2-(p-tolyloxy)ethyl)pyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)pyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(2-(3-(trifluoromethyl)phenoxy)ethyl)pyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)pyrrolidine;-   1-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethyl)pyridin-2(1H)-one;-   3-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)pyridine;-   5-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine;-   1-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethyl)pyridin-4(1H)-one;-   3-(4-chlorophenoxy)-1-(2-(cyclohexyloxy)ethyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(2-(naphthalen-1-yloxy)ethyl)pyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(2-(naphthalen-2-yloxy)ethyl)pyrrolidine;-   6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolone;-   6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)isoquinoline;-   7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)isoquinoline;-   7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolone;-   7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolin-2(1H)-one;-   6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)benzo[d]thiazole;-   6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)benzo[d]oxazole;-   1-(2-([1,1′-biphenyl]-3-yloxy)ethyl)-3-(4-chlorophenoxy)-3-methylpyrrolidine;-   6-(4-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)butoxy)benzo[d]thiazole;-   3-(4-chlorophenoxy)-3-methyl-1-(3-phenoxypropyl)pyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(4-phenoxybutyl)pyrrolidine;-   3-(4-chlorophenoxy)-1-(4-(2-fluorophenoxy)butyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-1-(4-(2-chlorophenoxy)butyl)-3-methylpyrrolidine;-   3-(4-chlorophenoxy)-3-methyl-1-(3-phenylpropyl)pyrrolidine;-   5-chloro-1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine];-   (3aS,9aR)-7-chloro-2-(2-phenoxyethyl)-1,2,3,3a,9,9a-hexahydrochromeno[2,3-c]pyrrole;-   4-((1-(2-phenoxyethyl)-3-phenylpyrrolidin-3-yl)oxy)aniline;-   3-(4-nitrophenoxy)-1-(2-phenoxyethyl)-3-phenylpyrrolidine;-   3-methyl-3-phenoxy-1-(2-phenoxyethyl)pyrrolidine;-   3-methyl-3-(2-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine;-   3-methyl-3-(3-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine;-   3-methyl-3-(4-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine;-   4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline;-   3-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline;-   2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline;-   3-methyl-1-(2-phenoxyethyl)-3-(o-tolyloxy)pyrrolidine;-   3-(2-methoxyphenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-(2-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-(3-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-(4-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-(2-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-(3-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-(2,3-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-(3,4-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-(2,4-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;-   3-methyl-1-(2-phenoxyethyl)-3-(2-(trifluoromethyl)phenoxy)pyrrolidine;-   3-methyl-1-(2-phenoxyethyl)-3-(3-(trifluoromethyl)phenoxy)pyrrolidine;-   3-methyl-1-(2-phenoxyethyl)-3-(4-(trifluoromethyl)phenoxy)pyrrolidine;-   2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine;-   3-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine;-   4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine;-   2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyrazine;-   4-(4-chlorophenoxy)-4-methyl-1-(2-phenoxyethyl)piperidine;-   4-(4-chlorophenoxy)-4-methyl-1-(4-phenoxybutyl)piperidine;-   4-methyl-4-phenoxy-1-(4-phenoxybutyl)piperidine;-   4-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethoxy)phenoxy)ethyl)piperidine;-   4-(4-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   4-(4-chlorophenoxy)-4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine;-   5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine;-   2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-5-(trifluoromethyl)pyridine;-   4-(4-chlorophenoxy)-4-methyl-1-(2-(4-(methylsulfonyl)phenoxy)ethyl)piperidine;-   1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethan-1-one;-   1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethan-1-ol;-   2-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)propan-2-ol;-   4-(4-chlorophenoxy)-1-(2-(4-fluorophenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(4-chlorophenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-4-methyl-1-(2-(p-tolyloxy)ethyl)piperidine;-   2-((4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)pyridine;-   4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(3-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-(methylsulfonyl)phenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine;-   1-(2-(5-chloro-2-(trifluoromethyl)phenoxy)ethyl)-4-(4-chlorophenoxy)-4-methylpiperidine;-   5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)thiazole;-   6-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)benzo[d]oxazole;-   7-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one;-   4-(benzyloxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine;-   3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-4-(trifluoromethyl)pyridine;-   4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine;-   3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine;-   2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-N-(2-(trifluoromethyl)phenyl)    acetamide;-   N-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-2-(trifluoromethyl)    aniline;-   N-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-N-methyl-2-(trifluoromethyl)aniline;-   N-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-N-(2-(trifluoromethyl)phenyl)    acetamide;-   1-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-8-(trifluoromethyl)quinolin-2(1H)-one;-   2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-8-(trifluoromethyl)quinolone;-   4-(4-chlorophenoxy)-1-(2-(cyclohexyloxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidine;-   1-(2-(2-fluorophenoxy)ethyl)-4-methyl-4-phenoxypiperidine;-   1-(2-(2-chlorophenoxy)ethyl)-4-methyl-4-phenoxypiperidine;-   4-methyl-4-phenoxy-1-(2-(o-tolyloxy)ethyl)piperidine;-   1-(2-(2-ethylphenoxy)ethyl)-4-methyl-4-phenoxypiperidine;-   1-(2-(2-isopropylphenoxy)ethyl)-4-methyl-4-phenoxypiperidine;-   1-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one;-   4-methyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   4-methyl-4-phenoxy-1-(2-(3-(trifluoromethyl)phenoxy)ethyl)piperidine;-   4-methyl-4-phenoxy-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine;-   1-(2-(5-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methyl-4-phenoxypiperidine;-   1-(2-(4-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methyl-4-phenoxypiperidine;-   4-methyl-4-phenoxy-1-(2-(2-(trifluoromethoxy)phenoxy)ethyl)piperidine;-   1-(2-(2-methoxyphenoxy)ethyl)-4-methyl-4-phenoxypiperidine;-   4-methyl-1-(2-(2-(methylsulfonyl)phenoxy)ethyl)-4-phenoxypiperidine;-   2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)benzonitrile;-   N,N-dimethyl-2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)aniline;-   2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)pyridine;-   4-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)pyridine;-   1-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethyl)pyridin-2(1H)-one;-   4-methyl-1-(2-(naphthalen-1-yloxy)ethyl)-4-phenoxypiperidine;-   4-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)-1H-indole;-   2-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)pyridine;-   4-(2-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   (1R,3r,5S)-3-methyl-3-phenoxy-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octane;-   (1R,3    s,5S)-3-methyl-3-phenoxy-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octane;-   1-(4-chlorophenyl)-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octane;-   2,4,6-trimethyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   4-methyl-1-(2-methyl-1-(2-(trifluoromethyl)phenoxy)propan-2-yl)-4-phenoxypiperidine;-   4-methyl-4-phenoxy-1-(1-(2-(trifluoromethyl)phenoxy)propan-2-yl)piperidine;-   4-methyl-4-phenoxy-1-(3-(2-(trifluoromethyl)phenyl)propyl)piperidine;-   4-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-2-(2-(trifluoromethyl)phenyl)butan-2-ol;-   3-(4-methyl-4-phenoxypiperidin-1-yl)-1-(2-(trifluoromethyl)phenyl)propan-1-one;-   1-phenyl-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octane;-   1-phenyl-7-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,7-diazaspiro[3.5]nonane;-   1-(4-chlorophenyl)-7-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,7-diazaspiro[3.5]nonane;-   1-(4-chlorophenyl)-7-(2-(2-fluorophenoxy)ethyl)-1,7-diazaspiro[3.5]nonane;-   1-(4-chlorophenyl)-8-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-1,8-diazaspiro[4.5]decane;-   1-(4-chlorophenyl)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,8-diazaspiro[4.5]decane;-   N,4-dimethyl-N-phenyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-amine;-   1′-(2-(2-(trifluoromethyl)phenoxy)ethyl)-3H-spiro[benzofuran-2,4′-piperidine];-   4-(hydroxy(phenyl)methyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol;-   2,2-dimethyl-4-phenyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,3-dioxa-8-azaspiro[4.5]decane;-   (4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)(phenyl)methanone;-   (4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)(phenyl)methanol;-   3-(4-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)piperidine;-   3-(4-chlorophenoxy)-3-methyl-1-(2-methyl-1-phenoxypropan-2-yl)piperidine;-   3-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-3-methylpiperidine;-   3-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-3-methylpiperidine;-   5-(2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)ethoxy)benzo[d]thiazole;-   3-methyl-1-(2-phenoxyethyl)-3-(3-(trifluoromethyl)phenoxy)piperidine;-   1-(2-(2-fluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine;-   1-(2-(2-chlorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine;-   4-methoxy-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol;-   3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-3-ol;-   (1R,3r,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol;-   (1R,3    s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol;-   3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)pyrrolidin-3-ol;-   4-methyl-1-(3-(2-(trifluoromethyl)phenoxy)propyl)piperidin-4-ol;-   4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol;-   4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol;-   4-methyl-1′-(2-(trifluoromethyl)phenyl)-[1,3′-bipiperidin]-4-ol;-   1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-ol;-   4-methyl-1-(2-phenoxyethyl)piperidin-4-ol;-   1-(2-(2-fluorophenoxy)ethyl)-4-methylpiperidin-4-ol;-   1-(2-phenoxyethyl)-3-phenylpyrrolidin-3-ol;-   1-(2-(2,5-difluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine,    or    -   a stereoisomer, racemate, tautomer, polymorph, hydrate, or        solvate thereof, or a pharmaceutically acceptable salt thereof.

Additional exemplary compounds of the invention include, but are notlimited to:3-(4-chlorophenoxy)-1-(2-(3-fluorophenoxy)ethyl)-3-methylpyrrolidine;

-   1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine];-   3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)pyridine;-   4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)pyridine;-   5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)phenol;-   4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)benzonitrile;-   1-(2-((1H-pyrazol-4-yl)oxy)ethyl)-4-(4-chlorophenoxy)-4-methylpiperidine;-   1-(2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-5-fluorophenyl)ethan-1-one;-   4-(4-chlorophenoxy)-1-(2-(2-methoxyphenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(4,5-difluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-isopropoxyphenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-isopropoxyphenoxy)ethyl)-4-methylpiperidine;-   4-(4-chlorophenoxy)-4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   4-(4-chlorophenoxy)-4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   4-ethynyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   1-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one;-   (1R,3    s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol;-   (1R,3r,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol;-   N,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxamide;-   N,4-dimethyl-1-(2-phenoxyethyl)piperidine-4-carboxamide;-   1-(2-(2-fluorophenoxy)ethyl)-N,4-dimethylpiperidine-4-carboxamide;-   1-(2-(2-methoxyphenoxy)ethyl)-N,4-dimethylpiperidine-4-carboxamide;-   1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,4-dimethylpiperidine-4-carboxamide;-   N-cyclopropyl-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidine-4-carboxamide;-   1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methyl-N-phenylpiperidine-4-carboxamide;-   (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,N,4-trimethylpiperidine-4-carboxamide;-   (S)-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)(pyrrolidin-1-yl)methanone;-   (S)-1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-N-methylmethanamine;-   (S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide;-   (S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)cyclopropanecarboxamide;-   (S)—N-(1-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide;-   (S)—N-(1-((7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide;-   (S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-2,2,2-trifluoroacetamide;-   (S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-N-methylacetamide;-   (4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)methanol;-   4-(4-chlorobenzyl)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;-   1-(4-chlorophenyl)-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octane;-   N-cyclohexyl-N,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-amine;-   4-methyl-N-phenyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxamide;-   1-(2-(2-fluorophenoxy)ethyl)-4-methyl-N-phenylpiperidine-4-carboxamide;    and stereoisomers, racemates, tautomers, polymorphs, hydrates,    solvates, and pharmaceutically acceptable salts thereof.

In certain embodiments, a compound of the invention is:

-   4-(4-Chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)    phenoxy)ethyl) piperidine (compound 90);-   4-(4-Chlorophenoxy)-4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)    piperidine (compound 125);-   4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine    (compound 157);-   1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,4-dimethylpiperidine-4-carboxamide    (compound 202);-   (S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide    (compound 208);-   (S)—N-(1-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide    (compound 210);    or a stereoisomer, racemate, tautomer, polymorph, hydrate, or    solvate thereof, or a pharmaceutically acceptable salt thereof.

The present invention relates to novel compounds that modulate dopamineD2 receptors. For example, compounds of the present invention have anEC₅₀<0.1 μM in the assay for 3-arrestin antagonist activity. Forexample, compounds of the present invention have an EC₅₀ of 0.1-1.0 μMin the assay for β-arrestin antagonist activity. For example, compoundsof the present invention have an EC₅₀ of 1.0-10.0 μM in the assay forβ-arrestin antagonist activity. For example, compounds of the presentinvention have an EC₅₀ of 10.0-30.0 μM in the assay for β-arrestinantagonist activity. Accordingly, compounds of the present invention areuseful in treating or preventing a disease or disorder in whichmodulation of D2 receptors plays a role.

For example, compounds of the present invention are selectiveantagonists of D2 receptors. For example, compounds of the presentinvention are selective β-arrestin antagonists, but not cAMPantagonists. For example, compounds of the present invention display atleast 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold,9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or100-fold stronger β-arrestin antagonist activity than cAMP antagonistactivity. For example, compounds of the present invention display atleast 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold,9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or100-fold decrease in EC₅₀ for β-arrestin antagonist activity than cAMPantagonist activity. Accordingly, compounds of the present invention areuseful in treating or preventing a disease or disorder in whichmodulation of D2 receptors plays a role, while at the same time, canreduce the undesirable side effects associated with D2 receptor activity(e.g., side effects arising from antagonizing the cAMP pathway).

For example, compounds of the present invention have an EC₅₀<0.1 μM inthe assay for β-arrestin antagonist activity and an EC₅₀≥0.1 μM in theassay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀<0.1 μM in the assay for β-arrestinantagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay for cAMPantagonist activity. For example, compounds of the present inventionhave an EC₅₀<0.1 μM in the assay for β-arrestin antagonist activity andan EC₅₀ of 1.0-10.0 μM in the assay for cAMP antagonist activity. Forexample, compounds of the present invention have an EC₅₀<0.1 μM in theassay for β-arrestin antagonist activity and an EC₅₀ of 10.0-30.0 μM inthe assay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀<0.1 μM in the assay for β-arrestinantagonist activity and an EC₅₀≥30.0 μM in the assay for cAMP antagonistactivity. Accordingly, compounds of the present invention are useful intreating or preventing a disease or disorder in which modulation of D2receptors plays a role, while at the same time, can reduce theundesirable side effects associated with D2 receptor activity (e.g.,side effects arising from antagonizing the cAMP pathway).

For example, compounds of the present invention have an EC₅₀ of 0.1-1.0μM in the assay for β-arrestin antagonist activity and an EC₅₀>1.0 μM inthe assay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestinantagonist activity and an EC₅₀ of 1.0-10.0 μM in the assay for cAMPantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestin antagonistactivity and an EC₅₀ of 10.0-30.0 μM in the assay for cAMP antagonistactivity. For example, compounds of the present invention have an EC₅₀of 0.1-1.0 μM in the assay for β-arrestin antagonist activity and anEC₅₀≥30.0 μM in the assay for cAMP antagonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role,while at the same time, can reduce the undesirable side effectsassociated with D2 receptor activity (e.g., side effects arising fromantagonizing the cAMP pathway).

For example, compounds of the present invention have an EC₅₀ of 1.0-10.0μM in the assay for β-arrestin antagonist activity and an EC₅₀>10.0 μMin the assay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of of 1.0-10.0 μM in the assay forβ-arrestin antagonist activity and an EC₅₀ of 10.0-30.0 μM in the assayfor cAMP antagonist activity. For example, compounds of the presentinvention have an EC₅₀ of of 1.0-10.0 μM in the assay for β-arrestinantagonist activity and an EC₅₀≥30.0 μM in the assay for cAMP antagonistactivity. Accordingly, compounds of the present invention are useful intreating or preventing a disease or disorder in which modulation of D2receptors plays a role, while at the same time, can reduce theundesirable side effects associated with D2 receptor activity (e.g.,side effects arising from antagonizing the cAMP pathway).

For example, compounds of the present invention have an EC₅₀ of of10.0-30.0 μM in the assay for β-arrestin antagonist activity and anEC₅₀>30.0 μM in the assay for cAMP antagonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role,while at the same time, can reduce the undesirable side effectsassociated with D2 receptor activity (e.g., side effects arising fromantagonizing the cAMP pathway).

For example, compounds of the present invention are selective β-arrestinantagonists and cAMP agonists. For example, compounds of the presentinvention have an EC₅₀<0.1 μM in the assay for β-arrestin antagonistactivity and an EC₅₀<0.1 μM in the assay for cAMP agonist activity. Forexample, compounds of the present invention have an EC₅₀<0.1 μM in theassay for β-arrestin antagonist activity and an EC₅₀ of 0.1-1.0 μM inthe assay for cAMP agonist activity.

For example, compounds of the present invention have an EC₅₀<0.1 μM inthe assay for β-arrestin antagonist activity and an EC₅₀ of 1.0-10.0 μMin the assay for cAMP agonist activity.

For example, compounds of the present invention have an EC₅₀<0.1 μM inthe assay for β-arrestin antagonist activity and an EC₅₀ of 10.0-30.0 μMin the assay for cAMP agonist activity.

Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role, while at the same time, can reduce the undesirable sideeffects associated with D2 receptor activity (e.g., side effects arisingfrom antagonizing the cAMP pathway).

For example, compounds of the present invention have an EC₅₀ of 0.1-1.0μM in the assay for β-arrestin antagonist activity and an EC₅₀<0.1 μM inthe assay for cAMP agonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestinantagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay for cAMPagonist activity. For example, compounds of the present invention havean EC₅₀ of 0.1-1.0 μM in the assay for β-arrestin antagonist activityand an EC₅₀ of 1.0-10.0 μM in the assay for cAMP agonist activity. Forexample, compounds of the present invention have an EC₅₀ of 0.1-1.0 μMin the assay for β-arrestin antagonist activity and an EC₅₀ of 10.0-30.0μM in the assay for cAMP agonist activity. Accordingly, compounds of thepresent invention are useful in treating or preventing a disease ordisorder in which modulation of D2 receptors plays a role, while at thesame time, can reduce the undesirable side effects associated with D2receptor activity (e.g., side effects arising from antagonizing the cAMPpathway).

For example, compounds of the present invention have an EC₅₀ of 1.0-10.0μM in the assay for β-arrestin antagonist activity and an EC₅₀<0.1 μM inthe assay for cAMP agonist activity. For example, compounds of thepresent invention have an EC₅₀ of 1.0-10.0 μM in the assay forβ-arrestin antagonist activity and an EC₅₀ of 0.1-1.0 μM in the assayfor cAMP agonist activity. For example, compounds of the presentinvention have an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestinantagonist activity and an EC₅₀ of 1.0-10.0 μM in the assay for cAMPagonist activity. For example, compounds of the present invention havean EC₅₀ of 1.0-10.0 μM in the assay for β-arrestin antagonist activityand an EC₅₀ of 10.0-30.0 μM in the assay for cAMP agonist activity.Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role, while at the same time, can reduce the undesirable sideeffects associated with D2 receptor activity (e.g., side effects arisingfrom antagonizing the cAMP pathway).

For example, compounds of the present invention have an EC₅₀ of10.0-30.0 μM in the assay for β-arrestin antagonist activity and anEC₅₀<0.1 μM in the assay for cAMP agonist activity. For example,compounds of the present invention have an EC₅₀ of 10.0-30.0 μM in theassay for β-arrestin antagonist activity and an EC₅₀ of 0.1-1.0 μM inthe assay for cAMP agonist activity. For example, compounds of thepresent invention have an EC₅₀ of 10.0-30.0 μM in the assay forβ-arrestin antagonist activity and an EC₅₀ of 1.0-10.0 μM in the assayfor cAMP agonist activity. For example, compounds of the presentinvention have an EC₅₀ of 10.0-30.0 μM in the assay for β-arrestinantagonist activity and an EC₅₀ of 10.0-30.0 μM in the assay for cAMPagonist activity. Accordingly, compounds of the present invention areuseful in treating or preventing a disease or disorder in whichmodulation of D2 receptors plays a role, while at the same time, canreduce the undesirable side effects associated with D2 receptor activity(e.g., side effects arising from antagonizing the cAMP pathway).

For example, compounds of the present invention are selective β-arrestinantagonists and agonists of cAMP and β-arrestin. Accordingly, compoundsof the present invention are useful in treating or preventing a diseaseor disorder in which modulation of D2 receptors plays a role, while atthe same time, can reduce the undesirable side effects associated withD2 receptor activity (e.g., side effects arising from antagonizing thecAMP pathway).

For example, compounds of the present invention are β-arrestinantagonists and cAMP antagonists. For example, compounds of the presentinvention have an EC₅₀<0.1 μM in the assay for β-arrestin antagonistactivity and an EC₅₀<0.1 μM in the assay for cAMP antagonist activity.For example, compounds of the present invention have an EC₅₀<0.1 μM inthe assay for β-arrestin antagonist activity and an EC₅₀ of 0.1-1.0 μMin the assay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestinantagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay for cAMPantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestin antagonistactivity and an EC₅₀ of 1.0-10.0 μM in the assay for cAMP antagonistactivity. For example, compounds of the present invention have an EC₅₀of 1.0-10.0 μM in the assay for β-arrestin antagonist activity and anEC₅₀ of 1.0-10.0 μM in the assay for cAMP antagonist activity. Forexample, compounds of the present invention have an EC₅₀ of of 1.0-10.0μM in the assay for β-arrestin antagonist activity and an EC₅₀ of10.0-30.0 μM in the assay for cAMP antagonist activity. For example,compounds of the present invention have an EC₅₀ of 10.0-30.0 μM in theassay for β-arrestin antagonist activity and an EC₅₀ of 10.0-30.0 μM inthe assay for cAMP antagonist activity. Accordingly, compounds of thepresent invention are useful in treating or preventing a disease ordisorder in which modulation of D2 receptors plays a role.

The present invention relates to novel compounds that modulate dopamineD2 receptors. For example, compounds of the present invention have anEC₅₀<0.1 μM in the assay for β-arrestin agonist activity. For example,compounds of the present invention have an EC₅₀ of 0.1-1.0 μM in theassay for β-arrestin agonist activity. For example, compounds of thepresent invention have an EC₅₀ of 1.0-10.0 μM in the assay forβ-arrestin agonist activity. For example, compounds of the presentinvention have an EC₅₀ of 10.0-30.0 μM in the assay for β-arrestinagonist activity. Accordingly, compounds of the present invention areuseful in treating or preventing a disease or disorder in whichmodulation of D2 receptors plays a role.

For example, compounds of the present invention are selective agonistsof D2 receptors. For example, compounds of the present invention areselective β-arrestin agonists, but not cAMP agonists. For example,compounds of the present invention display at least 1.5-fold, 2-fold,3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold,15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold strongerβ-arrestin agonist activity than cAMP agonist activity. For example,compounds of the present invention display at least 1.5-fold, 2-fold,3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold,15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold decrease inEC₅₀ for β-arrestin agonist activity than cAMP agonist activity.Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role.

For example, compounds of the present invention have an EC₅₀<0.1 μM inthe assay for β-arrestin agonist activity and an EC₅₀≥0.1 μM in theassay for cAMP agonist activity. For example, compounds of the presentinvention have an EC₅₀<0.1 μM in the assay for β-arrestin agonistactivity and an EC₅₀ of 0.1-1.0 μM in the assay for cAMP agonistactivity. For example, compounds of the present invention have anEC₅₀<0.1 μM in the assay for β-arrestin agonist activity and an EC₅₀ of1.0-10.0 μM in the assay for cAMP agonist activity. For example,compounds of the present invention have an EC₅₀<0.1 μM in the assay forβ-arrestin agonist activity and an EC₅₀ of 10.0-30.0 μM in the assay forcAMP agonist activity. For example, compounds of the present inventionhave an EC₅₀<0.1 μM in the assay for β-arrestin agonist activity and anEC₅₀≥30.0 μM in the assay for cAMP agonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of 0.1-1.0μM in the assay for β-arrestin agonist activity and an EC₅₀>1.0 μM inthe assay for cAMP agonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestinagonist activity and an EC₅₀ of 1.0-10.0 μM in the assay for cAMPagonist activity. For example, compounds of the present invention havean EC₅₀ of 0.1-1.0 μM in the assay for β-arrestin agonist activity andan EC₅₀ of 10.0-30.0 μM in the assay for cAMP agonist activity. Forexample, compounds of the present invention have an EC₅₀ of 0.1-1.0 μMin the assay for β-arrestin agonist activity and an EC₅₀≥30.0 μM in theassay for cAMP agonist activity. Accordingly, compounds of the presentinvention are useful in treating or preventing a disease or disorder inwhich modulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of 1.0-10.0μM in the assay for β-arrestin agonist activity and an EC₅₀>10.0 μM inthe assay for cAMP agonist activity. For example, compounds of thepresent invention have an EC₅₀ of of 1.0-10.0 μM in the assay forβ-arrestin agonist activity and an EC₅₀ of 10.0-30.0 μM in the assay forcAMP agonist activity. For example, compounds of the present inventionhave an EC₅₀ of of 1.0-10.0 μM in the assay for β-arrestin agonistactivity and an EC₅₀≥30.0 μM in the assay for cAMP agonist activity.Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role.

For example, compounds of the present invention have an EC₅₀ of of10.0-30.0 μM in the assay for β-arrestin agonist activity and anEC₅₀≥30.0 μM in the assay for cAMP agonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention are selective β-arrestinagonists and cAMP antagonists. For example, compounds of the presentinvention have an EC₅₀<0.1 μM in the assay for β-arrestin agonistactivity and an EC₅₀<0.1 μM in the assay for cAMP antagonist activity.For example, compounds of the present invention have an EC₅₀<0.1 μM inthe assay for β-arrestin agonist activity and an EC₅₀ of 0.1-1.0 μM inthe assay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀<0.1 μM in the assay for β-arrestinagonist activity and an EC₅₀ of 1.0-10.0 μM in the assay for cAMPantagonist activity. For example, compounds of the present inventionhave an EC₅₀<0.1 μM in the assay for β-arrestin agonist activity and anEC₅₀ of 10.0-30.0 μM in the assay for cAMP antagonist activity.Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role.

For example, compounds of the present invention have an EC₅₀ of 0.1-1.0μM in the assay for β-arrestin agonist activity and an EC₅₀<0.1 μM inthe assay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestinagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay for cAMPantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestin agonist activityand an EC₅₀ of 1.0-10.0 μM in the assay for cAMP antagonist activity.For example, compounds of the present invention have an EC₅₀ of 0.1-1.0μM in the assay for β-arrestin agonist activity and an EC₅₀ of 10.0-30.0μM in the assay for cAMP antagonist activity. Accordingly, compounds ofthe present invention are useful in treating or preventing a disease ordisorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of 1.0-10.0μM in the assay for β-arrestin agonist activity and an EC₅₀<0.1 μM inthe assay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 1.0-10.0 μM in the assay forβ-arrestin agonist activity and an EC₅₀ of 0.1-1.0 μM in the assay forcAMP antagonist activity. For example, compounds of the presentinvention have an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestinagonist activity and an EC₅₀ of 1.0-10.0 μM in the assay for cAMPantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestin agonist activityand an EC₅₀ of 10.0-30.0 μM in the assay for cAMP antagonist activity.Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role.

For example, compounds of the present invention have an EC₅₀ of10.0-30.0 μM in the assay for β-arrestin agonist activity and anEC₅₀<0.1 μM in the assay for cAMP antagonist activity. For example,compounds of the present invention have an EC₅₀ of 10.0-30.0 μM in theassay for β-arrestin agonist activity and an EC₅₀ of 0.1-1.0 μM in theassay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 10.0-30.0 μM in the assay forβ-arrestin agonist activity and an EC₅₀ of 1.0-10.0 μM in the assay forcAMP antagonist activity. For example, compounds of the presentinvention have an EC₅₀ of 10.0-30.0 μM in the assay for β-arrestinagonist activity and an EC₅₀ of 10.0-30.0 μM in the assay for cAMPantagonist activity. Accordingly, compounds of the present invention areuseful in treating or preventing a disease or disorder in whichmodulation of D2 receptors plays a role.

For example, compounds of the present invention are selective β-arrestinagonists and antagonists of cAMP and β-arrestin. Accordingly, compoundsof the present invention are useful in treating or preventing a diseaseor disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention are β-arrestin agonistsand cAMP agonists. For example, compounds of the present invention havean EC₅₀<0.1 μM in the assay for β-arrestin agonist activity and anEC₅₀<0.1 μM in the assay for cAMP agonist activity. For example,compounds of the present invention have an EC₅₀<0.1 μM in the assay forβ-arrestin agonist activity and an EC₅₀ of 0.1-1.0 μM in the assay forcAMP agonist activity. For example, compounds of the present inventionhave an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestin agonist activityand an EC₅₀ of 0.1-1.0 μM in the assay for cAMP agonist activity. Forexample, compounds of the present invention have an EC₅₀ of 0.1-1.0 μMin the assay for β-arrestin agonist activity and an EC₅₀ of 1.0-10.0 μMin the assay for cAMP agonist activity. For example, compounds of thepresent invention have an EC₅₀ of 1.0-10.0 μM in the assay forβ-arrestin agonist activity and an EC₅₀ of 1.0-10.0 μM in the assay forcAMP agonist activity. For example, compounds of the present inventionhave an EC₅₀ of of 1.0-10.0 μM in the assay for β-arrestin agonistactivity and an EC₅₀ of 10.0-30.0 μM in the assay for cAMP agonistactivity. For example, compounds of the present invention have an EC₅₀of 10.0-30.0 μM in the assay for β-arrestin agonist activity and an EC₅₀of 10.0-30.0 μM in the assay for cAMP agonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role,while at the same time, can reduce the undesirable side effectsassociated with D2 receptor activity (e.g., side effects arising fromantagonizing the cAMP pathway).

The present invention relates to novel compounds that modulate dopamineD2 receptors. For example, compounds of the present invention have anEC₅₀<0.1 μM in the assay for cAMP antagonist activity. For example,compounds of the present invention have an EC₅₀ of 0.1-1.0 μM in theassay for cAMP antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 1.0-10.0 μM in the assay for cAMPantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 10.0-30.0 μM in the assay for cAMP antagonist activity.Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role.

For example, compounds of the present invention are selectiveantagonists of D2 receptors. For example, compounds of the presentinvention are selective cAMP antagonists, but not β-arrestinantagnoists. For example, compounds of the present invention display atleast 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold,9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or100-fold stronger cAMP antagonist activity than β-arrestin antagonistactivity. For example, compounds of the present invention display atleast 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold,9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or100-fold decrease in EC₅₀ for cAMP antagonist activity than β-arrestinantagonist activity. Accordingly, compounds of the present invention areuseful in treating or preventing a disease or disorder in whichmodulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀<0.1 μM inthe assay for cAMP antagonist activity and an EC₅₀≥0.1 μM in the assayfor β-arrestin antagonist activity. For example, compounds of thepresent invention have an EC₅₀<0.1 μM in the assay for cAMP antagonistactivity and an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestinantagonist activity. For example, compounds of the present inventionhave an EC₅₀<0.1 μM in the assay for cAMP antagonist activity and anEC₅₀ of 1.0-10.0 μM in the assay for β-arrestin antagonist activity. Forexample, compounds of the present invention have an EC₅₀<0.1 μM in theassay for cAMP antagonist activity and an EC₅₀ of 10.0-30.0 μM in theassay for β-arrestin antagonist activity. For example, compounds of thepresent invention have an EC₅₀<0.1 μM in the assay for cAMP antagonistactivity and an EC₅₀≥30.0 μM in the assay for β-arrestin antagonistactivity. Accordingly, compounds of the present invention are useful intreating or preventing a disease or disorder in which modulation of D2receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of 0.1-1.0μM in the assay for cAMP antagonist activity and an EC₅₀>1.0 μM in theassay for β-arrestin antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for cAMPantagonist activity and an EC₅₀ of 1.0-10.0 μM in the assay forβ-arrestin antagonist activity. For example, compounds of the presentinvention have an EC₅₀ of 0.1-1.0 μM in the assay for cAMP antagonistactivity and an EC₅₀ of 10.0-30.0 μM in the assay for β-arrestinantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 0.1-1.0 μM in the assay for cAMP antagonist activity andan EC₅₀≥30.0 μM in the assay for β-arrestin antagonist activity.Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role.

For example, compounds of the present invention have an EC₅₀ of 1.0-10.0μM in the assay for cAMP antagonist activity and an EC₅₀>10.0 μM in theassay for β-arrestin antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of of 1.0-10.0 μM in the assay for cAMPantagonist activity and an EC₅₀ of 10.0-30.0 μM in the assay forβ-arrestin antagonist activity. For example, compounds of the presentinvention have an EC₅₀ of of 1.0-10.0 μM in the assay for cAMPantagonist activity and an EC₅₀≥30.0 μM in the assay for β-arrestinantagonist activity. Accordingly, compounds of the present invention areuseful in treating or preventing a disease or disorder in whichmodulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of of10.0-30.0 μM in the assay for cAMP antagonist activity and an EC₅₀>30.0μM in the assay for β-arrestin antagonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention are selective cAMPantagonists and β-arrestin agonists. For example, compounds of thepresent invention have an EC₅₀<0.1 μM in the assay for cAMP antagonistactivity and an EC₅₀<0.1 μM in the assay for β-arrestin agonistactivity. For example, compounds of the present invention have anEC₅₀<0.1 μM in the assay for cAMP antagonist activity and an EC₅₀ of0.1-1.0 μM in the assay for β-arrestin agonist activity. For example,compounds of the present invention have an EC₅₀<0.1 μM in the assay forcAMP antagonist activity and an EC₅₀ of 1.0-10.0 μM in the assay forβ-arrestin agonist activity. For example, compounds of the presentinvention have an EC₅₀<0.1 μM in the assay for cAMP antagonist activityand an EC₅₀ of 10.0-30.0 μM in the assay for β-arrestin agonistactivity. Accordingly, compounds of the present invention are useful intreating or preventing a disease or disorder in which modulation of D2receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of 0.1-1.0μM in the assay for cAMP antagonist activity and an EC₅₀<0.1 μM in theassay for β-arrestin agonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for cAMPantagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay forβ-arrestin agonist activity. For example, compounds of the presentinvention have an EC₅₀ of 0.1-1.0 μM in the assay for cAMP antagonistactivity and an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestin agonistactivity. For example, compounds of the present invention have an EC₅₀of 0.1-1.0 μM in the assay for cAMP antagonist activity and an EC₅₀ of10.0-30.0 μM in the assay for β-arrestin agonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of 1.0-10.0μM in the assay for cAMP antagonist activity and an EC₅₀<0.1 μM in theassay for β-arrestin agonist activity. For example, compounds of thepresent invention have an EC₅₀ of 1.0-10.0 μM in the assay for cAMPantagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay forβ-arrestin agonist activity. For example, compounds of the presentinvention have an EC₅₀ of 1.0-10.0 μM in the assay for cAMP antagonistactivity and an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestin agonistactivity. For example, compounds of the present invention have an EC₅₀of 1.0-10.0 μM in the assay for cAMP antagonist activity and an EC₅₀ of10.0-30.0 μM in the assay for β-arrestin agonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of10.0-30.0 μM in the assay for cAMP antagonist activity and an EC₅₀<0.1μM in the assay for β-arrestin agonist activity. For example, compoundsof the present invention have an EC₅₀ of 10.0-30.0 μM in the assay forcAMP antagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay forβ-arrestin agonist activity. For example, compounds of the presentinvention have an EC₅₀ of 10.0-30.0 μM in the assay for cAMP antagonistactivity and an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestin agonistactivity. For example, compounds of the present invention have an EC₅₀of 10.0-30.0 μM in the assay for cAMP antagonist activity and an EC₅₀ of10.0-30.0 μM in the assay for β-arrestin agonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention are selective cAMPantagonists and agonists of cAMP and β-arrestin. Accordingly, compoundsof the present invention are useful in treating or preventing a diseaseor disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention are cAMP antagonists andβ-arrestin antagonists. For example, compounds of the present inventionhave an EC₅₀<0.1 μM in the assay for cAMP antagonist activity and anEC₅₀<0.1 μM in the assay for β-arrestin antagonist activity. Forexample, compounds of the present invention have an EC₅₀<0.1 μM in theassay for cAMP antagonist activity and an EC₅₀ of 0.1-1.0 μM in theassay for β-arrestin antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for cAMPantagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay forβ-arrestin antagonist activity. For example, compounds of the presentinvention have an EC₅₀ of 0.1-1.0 μM in the assay for cAMP antagonistactivity and an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestinantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 1.0-10.0 μM in the assay for cAMP antagonist activityand an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestin antagonistactivity. For example, compounds of the present invention have an EC₅₀of of 1.0-10.0 μM in the assay for cAMP antagonist activity and an EC₅₀of 10.0-30.0 μM in the assay for β-arrestin antagonist activity. Forexample, compounds of the present invention have an EC₅₀ of 10.0-30.0 μMin the assay for cAMP antagonist activity and an EC₅₀ of 10.0-30.0 μM inthe assay for β-arrestin antagonist activity. Accordingly, compounds ofthe present invention are useful in treating or preventing a disease ordisorder in which modulation of D2 receptors plays a role.

The present invention relates to novel compounds that modulate dopamineD2 receptors. For example, compounds of the present invention have anEC₅₀<0.1 μM in the assay for cAMP agonist activity. For example,compounds of the present invention have an EC₅₀ of 0.1-1.0 μM in theassay for cAMP agonist activity. For example, compounds of the presentinvention have an EC₅₀ of 1.0-10.0 μM in the assay for cAMP agonistactivity. For example, compounds of the present invention have an EC₅₀of 10.0-30.0 μM in the assay for cAMP agonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention are selective agonistsof D2 receptors. For example, compounds of the present invention areselective cAMP agonists, but not β-arrestin agonists. For example,compounds of the present invention display at least 1.5-fold, 2-fold,3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold,15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold stronger cAMPagonist activity than β-arrestin agonist activity. For example,compounds of the present invention display at least 1.5-fold, 2-fold,3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold,15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold decrease inEC₅₀ for cAMP agonist activity than β-arrestin agonist activity.

For example, compounds of the present invention have an EC₅₀<0.1 μM inthe assay for cAMP agonist activity and an EC₅₀≥0.1 μM in the assay forβ-arrestin agonist activity. For example, compounds of the presentinvention have an EC₅₀<0.1 μM in the assay for cAMP agonist activity andan EC₅₀ of 0.1-1.0 μM in the assay for β-arrestin agonist activity. Forexample, compounds of the present invention have an EC₅₀<0.1 μM in theassay for cAMP agonist activity and an EC₅₀ of 1.0-10.0 μM in the assayfor β-arrestin agonist activity. For example, compounds of the presentinvention have an EC₅₀<0.1 μM in the assay for cAMP agonist activity andan EC₅₀ of 10.0-30.0 μM in the assay for β-arrestin agonist activity.For example, compounds of the present invention have an EC₅₀<0.1 μM inthe assay for cAMP agonist activity and an EC₅₀≥30.0 μM in the assay forβ-arrestin agonist activity. Accordingly, compounds of the presentinvention are useful in treating or preventing a disease or disorder inwhich modulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of 0.1-1.0μM in the assay for cAMP agonist activity and an EC₅₀>1.0 μM in theassay for β-arrestin agonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for cAMPagonist activity and an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestinagonist activity. For example, compounds of the present invention havean EC₅₀ of 0.1-1.0 μM in the assay for cAMP agonist activity and an EC₅₀of 10.0-30.0 μM in the assay for β-arrestin agonist activity. Forexample, compounds of the present invention have an EC₅₀ of 0.1-1.0 μMin the assay for cAMP agonist activity and an EC₅₀≥30.0 μM in the assayfor β-arrestin agonist activity. Accordingly, compounds of the presentinvention are useful in treating or preventing a disease or disorder inwhich modulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of 1.0-10.0μM in the assay for cAMP agonist activity and an EC₅₀>10.0 μM in theassay for β-arrestin agonist activity. For example, compounds of thepresent invention have an EC₅₀ of of 1.0-10.0 μM in the assay for cAMPagonist activity and an EC₅₀ of 10.0-30.0 μM in the assay for β-arrestinagonist activity. For example, compounds of the present invention havean EC₅₀ of of 1.0-10.0 μM in the assay for cAMP agonist activity and anEC₅₀≥30.0 μM in the assay for β-arrestin agonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention have an EC₅₀ of of10.0-30.0 μM in the assay for cAMP agonist activity and an EC₅₀≥30.0 μMin the assay for β-arrestin agonist activity. Accordingly, compounds ofthe present invention are useful in treating or preventing a disease ordisorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention are selective cAMPagonists and β-arrestin antagonists. For example, compounds of thepresent invention have an EC₅₀<0.1 μM in the assay for cAMP agonistactivity and an EC₅₀<0.1 μM in the assay for β-arrestin antagonistactivity. For example, compounds of the present invention have anEC₅₀<0.1 μM in the assay for cAMP agonist activity and an EC₅₀ of0.1-1.0 μM in the assay for β-arrestin antagonist activity. For example,compounds of the present invention have an EC₅₀<0.1 μM in the assay forcAMP agonist activity and an EC₅₀ of 1.0-10.0 μM in the assay forβ-arrestin antagonist activity. For example, compounds of the presentinvention have an EC₅₀<0.1 μM in the assay for cAMP agonist activity andan EC₅₀ of 10.0-30.0 μM in the assay for β-arrestin antagonist activity.Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role, while at the same time, can reduce the undesirable sideeffects associated with D2 receptor activity (e.g., side effects arisingfrom antagonizing the cAMP pathway).

For example, compounds of the present invention have an EC₅₀ of 0.1-1.0μM in the assay for cAMP agonist activity and an EC₅₀<0.1 μM in theassay for β-arrestin antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 0.1-1.0 μM in the assay for cAMPagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestinantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 0.1-1.0 μM in the assay for cAMP agonist activity and anEC₅₀ of 1.0-10.0 μM in the assay for β-arrestin antagonist activity. Forexample, compounds of the present invention have an EC₅₀ of 0.1-1.0 μMin the assay for cAMP agonist activity and an EC₅₀ of 10.0-30.0 μM inthe assay for β-arrestin antagonist activity. Accordingly, compounds ofthe present invention are useful in treating or preventing a disease ordisorder in which modulation of D2 receptors plays a role, while at thesame time, can reduce the undesirable side effects associated with D2receptor activity (e.g., side effects arising from antagonizing the cAMPpathway).

For example, compounds of the present invention have an EC₅₀ of 1.0-10.0μM in the assay for cAMP agonist activity and an EC₅₀<0.1 μM in theassay for β-arrestin antagonist activity. For example, compounds of thepresent invention have an EC₅₀ of 1.0-10.0 μM in the assay for cAMPagonist activity and an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestinantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 1.0-10.0 μM in the assay for cAMP agonist activity andan EC₅₀ of 1.0-10.0 μM in the assay for β-arrestin antagonist activity.For example, compounds of the present invention have an EC₅₀ of 1.0-10.0μM in the assay for cAMP agonist activity and an EC₅₀ of 10.0-30.0 μM inthe assay for β-arrestin antagonist activity. Accordingly, compounds ofthe present invention are useful in treating or preventing a disease ordisorder in which modulation of D2 receptors plays a role, while at thesame time, can reduce the undesirable side effects associated with D2receptor activity (e.g., side effects arising from antagonizing the cAMPpathway).

For example, compounds of the present invention have an EC₅₀ of10.0-30.0 μM in the assay for cAMP agonist activity and an EC₅₀<0.1 μMin the assay for β-arrestin antagonist activity. For example, compoundsof the present invention have an EC₅₀ of 10.0-30.0 μM in the assay forcAMP agonist activity and an EC₅₀ of 0.1-1.0 μM in the assay forβ-arrestin antagonist activity. For example, compounds of the presentinvention have an EC₅₀ of 10.0-30.0 μM in the assay for cAMP agonistactivity and an EC₅₀ of 1.0-10.0 μM in the assay for β-arrestinantagonist activity. For example, compounds of the present inventionhave an EC₅₀ of 10.0-30.0 μM in the assay for cAMP agonist activity andan EC₅₀ of 10.0-30.0 μM in the assay for β-arrestin antagonist activity.Accordingly, compounds of the present invention are useful in treatingor preventing a disease or disorder in which modulation of D2 receptorsplays a role, while at the same time, can reduce the undesirable sideeffects associated with D2 receptor activity (e.g., side effects arisingfrom antagonizing the cAMP pathway).

For example, compounds of the present invention are selective cAMPagonists and antagonists of cAMP and β-arrestin. Accordingly, compoundsof the present invention are useful in treating or preventing a diseaseor disorder in which modulation of D2 receptors plays a role.

For example, compounds of the present invention are cAMP agonists andβ-arrestin agonists. For example, compounds of the present inventionhave an EC₅₀<0.1 μM in the assay for cAMP agonist activity and anEC₅₀<0.1 μM in the assay for β-arrestin agonist activity. For example,compounds of the present invention have an EC₅₀<0.1 μM in the assay forcAMP agonist activity and an EC₅₀ of 0.1-1.0 μM in the assay forβ-arrestin agonist activity. For example, compounds of the presentinvention have an EC₅₀ of 0.1-1.0 μM in the assay for cAMP agonistactivity and an EC₅₀ of 0.1-1.0 μM in the assay for β-arrestin agonistactivity. For example, compounds of the present invention have an EC₅₀of 0.1-1.0 μM in the assay for cAMP agonist activity and an EC₅₀ of1.0-10.0 μM in the assay for β-arrestin agonist activity. For example,compounds of the present invention have an EC₅₀ of 1.0-10.0 μM in theassay for cAMP agonist activity and an EC₅₀ of 1.0-10.0 μM in the assayfor β-arrestin agonist activity. For example, compounds of the presentinvention have an EC₅₀ of of 1.0-10.0 μM in the assay for cAMP agonistactivity and an EC₅₀ of 10.0-30.0 μM in the assay for β-arrestin agonistactivity. For example, compounds of the present invention have an EC₅₀of 10.0-30.0 μM in the assay for cAMP agonist activity and an EC₅₀ of10.0-30.0 μM in the assay for β-arrestin agonist activity. Accordingly,compounds of the present invention are useful in treating or preventinga disease or disorder in which modulation of D2 receptors plays a role.

Abbreviations

-   Binap 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   Boc: tert-butyloxycarbonyl-   t-BuOK: potassium tert-butoxide-   DAST: diethylaminosulfur trifluoride-   Dba: Dibenzylideneacetone-   DCM: Dichloromethane-   DIPEA: N,N-diisopropylethylamine-   DMF: N,N-dimethylformamide-   DMP: Dess Martin periodinane-   DMSO: Dimethylsulfoxide-   DMU: N-Nitroso-N-methylurea-   EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et₂O: diethyl ether-   EtOAc: ethyl acetate-   EtOH: Ethanol-   Et₃N: Triethylamine-   Fmoc: 9-fluorenylmethoxycarbonyl-   HATU:    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate,    N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium    hexafluorophosphate N-oxide-   HOBt: Hydroxybenzotriazole-   LAH: lithium aluminium hydride-   MeOH: Methanol-   [O]: oxidation using suitable oxidants such as Dess Martin    periodinane, pyridinium chlorochromate, pyridinium dichromate, or    oxidation reagents used in Swern oxidation, Parikh-Doering    oxidation, Corey-Kim oxidation or Pfitzner-Moffatt oxidation-   MS: mass spectrometry-   MsCl: Methanesulfonyl chloride-   Pd(OAc)₂: Palladium(II) acetate-   TPP: Triphenyl phosphine-   THF: Tetrahydrofuran-   TFA: trifluoroacetic acid

The terms “compounds of the invention”, “compound of the invention”,“compounds of the present invention” and “compounds of the presentinvention”, and the like, unless the context indicates otherwise, refercollectively to the novel compounds of any formulae or specificcompounds described herein, and their salts, solvates, stereoisomers,tautomers, racemates, polymorphs and hydrates.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁-C₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl. Forexample “1-6” is intended to encompass, 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4,1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6.

As used herein, the term “halogen” refers to fluorine, chlorine, bromineor iodine.

As used herein, the term “alkyl” refers to a radical of a straight-chainor branched saturated hydrocarbon group having from 1 to 20 carbon atoms(“C₁-C₂₀ alkyl”). In some embodiments, an alkyl group has 1 to 10 carbonatoms (“C₁-C₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9carbon atoms (“C₁-C₉ alkyl”). In some embodiments, an alkyl group has 1to 8 carbon atoms (“C₁-C₈ alkyl”). In some embodiments, an alkyl grouphas 1 to 7 carbon atoms (“C₁-C₇ alkyl”). In some embodiments, an alkylgroup has 1 to 6 carbon atoms (“C₁-C₆ alkyl”). In some embodiments, analkyl group has 1 to 5 carbon atoms (“C₁-C₅ alkyl”). In someembodiments, an alkyl group has 1 to 4 carbon atoms (“C₁-C₄ alkyl”). Insome embodiments, an alkyl group has 1 to 3 carbon atoms (“C₁-C₃alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms(“C₁-C₂ alkyl”). In some embodiments, an alkyl group has 1 carbon atom(“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbonatoms (“C₂-C₆ alkyl”). Examples of C₁-C₆ alkyl groups include methyl(C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄),tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyoptionally substituted, e.g., unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents.

The term “substituted alkyl” refers to alkyl moieties havingsubstituents replacing one or more hydrogen atoms on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino(including alkylamino, dialkylamino, arylamino, diarylamino andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.Cycloalkyls can be further substituted, e.g., with the substituentsdescribed above. An “alkylaryl” or an “aralkyl” moiety is an alkylsubstituted with an aryl (e.g., phenylmethyl (benzyl)).

The term “haloalkyl” is a substituted alkyl group, wherein one or moreof the hydrogen atoms are independently replaced by a halogen, e.g.,fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkylmoiety has 1 to 8 carbon atoms (“C₁-C₈ haloalkyl”). In some embodiments,the haloalkyl moiety has 1 to 6 carbon atoms (“C₁-C₆ haloalkyl”). Insome embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C₁-C₄haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbonatoms (“C₁-C₃ haloalkyl”). In some embodiments, the haloalkyl moiety has1 to 2 carbon atoms (“C₁-C₂ haloalkyl”). Examples of haloalkyl groupsinclude —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂,—CF₂Cl, and the like.

The term “alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In someembodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”).In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently unsubstituted (an “unsubstitutedalkenyl”) or substituted (a “substituted alkenyl”) with one or moresubstituents. In certain embodiments, the alkenyl group is anunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis a substituted C₂₋₁₀ alkenyl. In an alkenyl group, a C═C double bondfor which the stereochemistry is not specified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

The term “alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently unsubstituted (an “unsubstitutedalkynyl”) or substituted (a “substituted alkynyl”) with one or moresubstituents. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

As used herein, the term “cyclic ring” or “cyclic group” refers to asaturated or unsaturated carbocyclic ring, i.e., a ring composedexclusively of carbon atoms, or to a saturated or unsaturatedheterocyclic ring, i.e., a carbocyclic ring wherein one or more ringatoms are replaced with an heteroatom independently selected fromoxygen, nitrogen, and sulfur. Cyclic rings may involve 3-10 atoms thatform the ring. In some embodiments, the cyclic rings involve 3-5 ringatoms, in other embodiments, the cyclic rings involve 4-6 ring atoms, inyet other embodiments, cyclic rings involve 5-7 ring atoms. The cyclicrings can be monocyclic rings or fused systems that may include bicyclicrings, for example, 5-5, 5-6, 6-5, 6-6 as well as spirocyclic systemssuch as 4-4, 4-5, 4-6, 5-6 and 6-6. The cyclic ring may be furthersubstituted with substituents such as C₁-C₆ alkyl (linear, branched,cyclic or heterocyclic): In some embodiments, cyclic groups may includepseudo-cyclic groups comprising straight- or branched substituted orsubstituted alkyl groups, for example C₃-C₁₀ alkyl groups.

As used herein, the term “cycloalkyl” refers to a saturated orunsaturated cyclic monovalent hydrocarbon, containing one or two ringsand comprising 3-10 ring atoms, preferably 4-8 ring atoms, and morepreferably 5-6 ring carbon atoms. Examples of a cycloalkyl useful in thecontext of the present invention are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferablycyclopentyl and cyclohexyl, more preferably cyclohexyl. Cycloalkyl alsoincludes hydrocarbon spirocyclique groups.

As used herein, the term “heterocyclyl” refers to a saturated orunsaturated cycloalkyl wherein one or more ring atoms are replaced withan heteroatom independently selected from oxygen, nitrogen, and sulfur.The term heterocyclyl also encompasses partially hydrogenated and oxoderivatives of heteroaryl compounds. Examples of a heterocyclyl usefulin the context of the present invention are pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, anddithiolanyl.

As used herein, the term “bicyclic group” refers to a group containingtwo cyclic groups, with 5-12 or 6-12 ring atoms, optionally containing1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur,said two cyclic groups being fused or bridged or forming a spirocycle.Preferably, the two cyclic groups are fused and one of the two cyclicgroups is a phenyl while the other is a cycloalkyl or heterocycloalkyl,wherein the phenyl, cycloalkyl and heterocycloalkyl are independentlyoptionally substituted. Examples of a bicyclic group useful in thecontext of the present invention are oxo-tetrahydroquinolinyl,benzodioxolyl, difluorobenzodioxolyl and dihydroindenyl. Each cycle inthe bicyclic group can be independently aromatic, unsaturated, partiallysaturated, or saturated.

As used herein, the term “spirocycle” refers to a bicyclic compoundwherein the two cyclic groups connect only through one atom.

Further examples of bicyclic groups include bridged ring systems such asbicycloalkanes and azabicycloalkanes although such bridged ring systemsare generally less preferred. By “bridged ring systems” is meant ringsystems in which two rings share more than two atoms, see for exampleAdvanced Organic Chemistry, by Jerry March, 4th. Edition, WileyInterscience, pages 131-133, 1992. Examples of bridged ring systemsinclude bicyclo[2.2.1]heptane, aza-bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, aza-bicyclo[2.2.2]octane, bicyclo[3.2.1]octane andaza-bicyclo[3.2.1]octane. A particular example of a bridged ring systemis the 1-aza-bicyclo[2.2.2]octan-3-yl group.

As used herein, the term “aryl” refers to a polyunsaturated aromaticcarbocyclic group comprising one ring (i.e., phenyl) or several fusedrings (for example naphthyl) or several rings linked via a covalent bond(for example biphenyl), which typically contain 5 to 12 andpreferentially 6 to 10 carbon atoms, and wherein at least one ring isaromatic. Examples of an aryl useful in the context of the presentinvention are phenyl, naphtyl and biphenyl, preferably phenyl.

As used herein, the term “heteroaryl” refers to an aryl containing 1-4ring heteroatoms independently selected from nitrogen, oxygen, andsulfur. The nitrogen heteroatom may be substituted or unsubstituted withsubstituents, for example with an alkyl group and/or the nitrogenheteroatom may be derivatised to form a salt or amine oxide. Examples ofa heteroaryl useful in the context of the present invention are furyl,thienyl, pyrrolyl, pyranyl, thiopyranyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, quinolinyl,isoquinolinyl, indolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, benzoimidazolyl and benzopyrazole,preferably pyridyl, quinolinyl, benzofuranyl, benzoxazolyl andbenzothiazolyl.

The terms “aryl” and “heteroaryl” include multicyclic aryl andheteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene,benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline,naphthridine, indole, benzofuran, purine, benzofuran, deazapurine, andindolizine. In the case of multicyclic aromatic rings, only one of therings needs to be aromatic (e.g., 2,3-dihydroindole), although all ofthe rings may be aromatic (e.g., quinoline). The second ring can also befused or bridged.

The aryl or heteroaryl aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,alkyl, alkenyl, akynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl,alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,phosphate, phosphonato, phosphinato, amino (including alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Aryl groups can also be fused or bridged withalicyclic or heterocyclic rings, which are not aromatic so as to form amulticyclic system (e.g., tetralin, methylenedioxyphenyl).

As used herein, “carbocycle” or “carbocyclic ring” is intended toinclude any stable monocyclic, bicyclic or tricyclic ring having thespecified number of carbons, any of which may be saturated, unsaturated,or aromatic. For example, a C₃-C₁₄ carbocycle is intended to include amonocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13 or 14 carbon atoms.

Examples of carbocycles include, but are not limited to, cyclopropyl,cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl,cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl,cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl,adamantyl and tetrahydronaphthyl. Bridged rings are also included in thedefinition of carbocycle, including, for example, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane and [2.2.2]bicyclooctane. Abridged ring occurs when one or more carbon atoms link two non-adjacentcarbon atoms. In one embodiment, bridge rings are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge. Fused (e.g., naphthyl,tetrahydronaphthyl) and spiro rings are also included.

As used herein, “heterocycle” includes any ring structure (saturated orpartially unsaturated) which contains at least one ring heteroatom(e.g., N, O or S). Examples of heterocycles include, but are not limitedto, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazineand tetrahydrofuran. Examples of heterocyclic groups include, but arenot limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyl,oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

The term “x- to y-membered ring” (wherein x is an integer independentlyselected from 3, 4, 5, 6, 7, and 8, preferably from 3, 4, and 5, andmore preferably from 3 and 4; and y is an integer independently selectedfrom 4, 5, 6, 7, 8, 9, 10, 11, and 12, preferably from 5, 6, 7, 8, and9, and 10) includes cyclic ring, cyclic group, carbocycle, heterocycle,aryl, and heteroaryl, each having x- to y-number of ring atoms, asdefined herein.

The term “alkoxy” or “alkoxyl” includes substituted and unsubstitutedalkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.Examples of alkoxy groups or alkoxyl radicals include, but are notlimited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxygroups. Examples of substituted alkoxy groups include halogenated alkoxygroups. The alkoxy groups can be substituted with groups such asalkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkylamino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

The term “substituted”, as used herein, means that any one or morehydrogen atoms on the designated atom is replaced with a selection fromthe indicated groups, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogen atoms on the atomare replaced. Keto substituents are not present on aromatic moieties.Ring double bonds, as used herein, are double bonds that are formedbetween two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchformula. Combinations of substituents and/or variables are permissible,but only if such combinations result in stable compounds.

When any variable (e.g., R₁) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R₁ moieties,then the group may optionally be substituted with up to two R₁ moietiesand R₁ at each occurrence is independently selected independently fromthe definition of R₁. Also, combinations of substituents and/orvariables are permissible, but only if such combinations result instable compounds.

Except as described herein, any of the above defined alkyl, cycloalkyl,aryl, heteroaryl, carbocycle, heterocycle, and alkoxy, may beunsubstituted or independently substituted with up to six, preferablyone, two or three substituents, independently selected from the groupconsisting of: halo (such as F, Cl or Br); hydroxy; lower alkyl (such asC₁-C₆ alkyl, C₁-C₃ alkyl), wherein the lower alkyl may be substitutedwith any of the substituents defined herein; lower alkanoyl; loweralkoxy (such as methoxy); aryl (such as phenyl or naphthyl); substitutedaryl (such as fluoro phenyl or methoxy phenyl); aryl lower alkyl such asbenzyl; amino; mono or di-lower alkyl amino (such as dimethylamino);lower alkanoyl amino acetylamino; amino lower alkoxy (such asethoxyamine); nitro; cyano; cyano lower alkyl; carboxy; lower carbalkoxy(such as methoxy carbonyl; n-propoxy carbonyl or iso-propoxy carbonyl);lower aryloyl, such as benzoyl; carbamoyl; N-mono- or N,N di-lower alkylcarbamoyl; lower alkyl carbamic acid ester; amidino; guanidine; ureido;mercapto; sulfo; lower alkylthio; sulfoamino; sulfonamide;benzosulfonamide; sulfonate; sulfanyl lower alkyl (such as methylsulfanyl); sulfoamino; aryl sulfonamide; halogen substituted orunsubstituted aryl sulfonate (such as chloro-phenyl sulfonate); loweralkylsulfinyl; arylsulfinyl; aryl-lower alkylsulfinyl; loweralkylarylsulfinyl; lower alkanesulfonyl; arylsulfonyl; aryl-loweralkylsulfonyl; lower aryl alkyl; lower alkylarylsulfonyl; halogen-loweralkylmercapto; halogen-lower alkylsulfonyl; such as trifluoromethanesulfonyl; phosphono(-P(═O)(OH)₂); hydroxy-lower alkoxy phosphoryl ordi-lower alkoxyphosphoryl; urea and substituted urea; and alkyl carbamicacid ester or carbamates (such as ethyl-N-phenyl-carbamate).

The compounds of the present invention are capable of further formingsalts. All of these forms are also contemplated within the scope of theclaimed invention.

As used herein, a salt of the compound of the invention refers toderivatives of the compounds of the present invention wherein the parentcompound is modified by making acid or base salts thereof. Examples ofsalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines, alkali or organic salts of acidicresidues such as carboxylic acids, and the like. The salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include, but arenot limited to, those derived from inorganic and organic acidsindependently selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic,acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic,citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric,glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic,hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic,hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric,oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and thecommonly occurring amine acids, e.g., glycine, alanine, phenylalanine,arginine, etc.

Other examples of salts of the compounds of the invention include saltswith the following acid: hexanoic acid, cyclopentane propionic acid,pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamicacid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, andthe like. The present invention also encompasses salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base such as ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like.

The free base of the compounds of the present invention can beprotonated at the N atom(s) of an amine and/or N containing heterocyclemoiety to form a salt. The term “free base” refers to the aminecompounds in non-salt form. The free form of the specific salt compoundsdescribed may be isolated using techniques known in the art. Forexample, the free form may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous sodiumhydroxide, potassium carbonate, ammonia and sodium bicarbonate. The freeforms may differ from their respective salt forms somewhat in certainphysical properties, such as solubility in polar solvents, but the acidand base salts are otherwise pharmaceutically equivalent to theirrespective free forms for purposes of the invention.

The salts can be synthesized from the compounds of the invention whichcontain basic moieties by conventional chemical methods. Generally, thesalts of the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents.

The salts of the instant invention can be prepared from compounds of theinvention by reacting with an inorganic, organic acid or polymeric acid.For example, conventional non-toxic salts include those derived fromacids such as hydrochloric acid, toluenesulfonic acid, sulfuric acid,benzenesulfonic acid, fumaric acid or succinic acid, especiallytoluenesulfonic acid, pamoic acid (see for example, WO2005/016261; U.S.Pat. No. 6,987,111; US 20050032836; US 20060040922).

Compounds of the present invention that contain nitrogens can beconverted to N-oxides by treatment with an oxidizing agent (e.g.,3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxides) to affordother compounds of the present invention. Thus, all shown and claimednitrogen-containing compounds are considered, when allowed by valencyand structure, to include both the compound as shown and its N-oxidederivative (which can be designated as N→O or N⁺—O⁻). Furthermore, inother instances, the nitrogens in the compounds of the present inventioncan be converted to N-hydroxy or N-alkoxy compounds. For example,N-hydroxy compounds can be prepared by oxidation of the parent amine byan oxidizing agent such as m-CPBA. All shown and claimednitrogen-containing compounds are also considered, when allowed byvalency and structure, to cover both the compound as shown and itsN-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, wherein R issubstituted or unsubstituted C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl,3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent invention includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In addition, a crystal polymorphism may bepresent for the compounds represented by the formula. It is noted thatany crystal form, crystal form mixture, or anhydride or hydrate thereofis included in the scope of the present invention. Furthermore,so-called metabolite which is produced by degradation of the presentcompound in vivo is included in the scope of the present invention.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four nonidentical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisinvention include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose. Common tautomeric pairs are:ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerismin heterocyclic rings (e.g., in nucleobases such as guanine, thymine andcytosine), amine-enamine and enamine-enamine.

It is to be understood that the compounds of the present invention maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present invention, and the naming ofthe compounds does not exclude any tautomer form.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or a salt or solvate thereof)can crystallize in different crystal packing arrangements, all of whichhave the same elemental composition. Different crystal forms usuallyhave different X-ray diffraction patterns, infrared spectral, meltingpoints, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

Additionally, the compounds of the present invention, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules. Nonlimitingexamples of hydrates include monohydrates, dihydrates, etc. Nonlimitingexamples of solvates include ethanol solvates, acetone solvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the “parent drug” or “parent molecule”)that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

The compounds of the present invention can also be prepared as prodrugs,for example, pharmaceutically acceptable prodrugs. The terms “pro-drug”and “prodrug” are used interchangeably herein and refer to any compoundwhich releases an active parent drug in vivo. Since prodrugs are knownto enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.), the compounds of thepresent invention can be delivered in prodrug form. Thus, the presentinvention is intended to cover prodrugs of the presently claimedcompounds, methods of delivering the same and compositions containingthe same. “Prodrugs” are intended to include any covalently bondedcarriers that release an active parent drug of the present invention invivo when such prodrug is administered to a subject. Prodrugs in thepresent invention are prepared by modifying functional groups present inthe compound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound. Prodrugsinclude compounds of the present invention wherein a hydroxy, amino,sulfhydryl, carboxy or carbonyl group is bonded to any group that may becleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl,free carboxy or free carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters (e.g.,acetate, dialkylaminoacetates, formates, phosphates, sulfates andbenzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy functional groups, esters (e.g., ethyl esters,morpholinoethanol esters) of carboxyl functional groups, N-acylderivatives (e.g., N-acetyl)N-Mannich bases, Schiff bases and enaminonesof amino functional groups, oximes, acetals, ketals and enol esters ofketone and aldehyde functional groups in compounds of the invention, andthe like, See Bundegaard, H., Design of Prodrugs, p 1-92, Elesevier, NewYork-Oxford (1985).

As used herein, the term “combination”, as applied to two or morecompounds and/or agents (also referred to herein as the components), isintended to define material in which the two or more compounds/agentsare associated. The terms “combined” and “combining” in this context areto be interpreted accordingly.

As used herein, the term “in combination” may refer to compounds/agentsthat are administered as part of the same overall treatment regimen. Assuch, the posology of each of the two or more compounds/agents maydiffer: each may be administered at the same time or at different times.It will therefore be appreciated that the compounds/agents of thecombination may be administered sequentially (e.g., before or after) orsimultaneously, either in the same pharmaceutical formulation (i.e.,together), or in different pharmaceutical formulations (i.e.,separately). Simultaneously in the same formulation is as a unitaryformulation whereas simultaneously in different pharmaceuticalformulations is non-unitary. The posologies of each of the two or morecompounds/agents in a combination therapy may also differ with respectto the route of administration.

The term “drug” or “active substance” as used herein includes the freebase, or pharmaceutically acceptable salts, solvates, stereoisomers,racemates, tautomers, polymorphs and hydrates thereof, or mixturesthereof.

As used herein, the term “selective” when used to describe β-arrestinantagonist, β-arrestin agonist, cAMP antagonist, or cAMP agonist means“biased” β-arrestin antagonist, β-arrestin agonist, cAMP antagonist, orcAMP agonist, unless the specific circumstances dictate otherwise (i.e.,“selective” and “biased” are used interchangeably). The term “selective”or “biased” means that a compound preferentially binds to or otherwiseinteracts with one of β-arrestin and cAMP over the other. For example,the compound binds to or otherwise interacts with one of β-arrestin andcAMP with an EC₅₀ that is lower that the EC₅₀ for the other, such asdescribed herein.

Synthesis of the Compounds of the Invention

The present invention provides methods for the synthesis of thecompounds of each of the formulae described herein. The presentinvention also provides detailed methods for the synthesis of variousdisclosed compounds of the present invention according to the followingschemes and examples.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where methods or processes are described ashaving, including, or comprising specific process steps, the processesalso consist essentially of, or consist of, the recited processingsteps. Further, it should be understood that the order of steps or orderfor performing certain actions is immaterial so long as the inventionremains operable. Moreover, two or more steps or actions can beconducted simultaneously.

The synthetic processes of the invention can tolerate a wide variety offunctional groups, therefore various substituted starting materials canbe used. The processes generally provide the desired final compound ator near the end of the overall process, although it may be desirable incertain instances to further convert the compound to a pharmaceuticallyacceptable salt, ester or prodrug thereof.

Compounds of the present invention can be prepared in a variety of waysusing commercially available starting materials, compounds known in theliterature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentinvention.

Compounds of the present invention can be conveniently prepared by avariety of methods familiar to those skilled in the art. The compoundseach of the formulae described herein may be prepared according to thefollowing procedure, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art from commercially available starting materialsor starting materials which can be prepared using literature procedures.These procedures show the preparation of representative compounds of theinvention.

All the abbreviations used in this application are found in “ProtectiveGroups in Organic Synthesis” by John Wiley & Sons, Inc, or the MERCKINDEX by MERCK & Co., Inc, or other chemistry books or chemicalscatalogs by chemicals vendor such as Aldrich, or according to usage knowin the art.

Preferred methods include but are not limited to those methods describedbelow. Compounds of the present invention can be synthesized byfollowing the steps outlined in General Scheme 1 which comprisedifferent sequences of assembling intermediates Ia, Ib, Ic, Id, Ie, If,Ig, Ih, Ii, Ik, and Il. Starting materials are either commerciallyavailable or made by known procedures in the reported literature or asillustrated.

The general way of preparing target molecules I by using intermediatesIa, Ib, Ic, Id, Ie, Ig, Ih, Ii, Ik, and Il is outlined in GeneralScheme 1. Nucleophilic addition of Ia to Ib using a base, i.e.,potassium carbonate (K₂CO₃) or sodium hydroxide (NaOH), in solvent,i.e., acetone or water, at elevated temperatures provides intermediateIc. Alkylation of ketone Id with Grignard reagent Ie in a solvent, i.e.,tetrahydrofuran or diethylether, provides intermediate If. Removal ofthe amine protecting group, i.e., di-tert-butyl dicarbonate, of Ifyields intermediate Ig. Alkylation of Ig with intermediate Ic using abase, i.e., potassium carbonate (K₂CO₃), in solvent, i.e., acetonitrile,at elevated temperatures provides intermediate Ih. Alkylation of Ih withintermediate Ii using a base, i.e., sodium hydride, in solvent, i.e.,tetrahydrofuran, at elevated temperatures provides the compound ofFormula (I). Alternatively, treatment of intermediate If withintermediate Ii and a base, i.e., sodium hydride, in solvent, i.e.,tetrahydrofuran, at elevated temperatures provides intermediate Ik.Subsequent removal of the amine protecting group, i.e., di-tert-butyldicarbonate, of Ik yields intermediate II. Alkylation of Il withintermediate Ic using a base, i.e., potassium carbonate (K₂CO₃), insolvent, i.e., acetonitrile, at elevated temperatures provides thecompound of Formula (I).

Assays for Activities of the Compounds of the Invention

The present invention provides methods for assessing the in vitro and invivo biological activities (e.g., antagonistic or agonistic activities)of the compounds of the invention. Biological activities (e.g.,antagonistic or agonistic activities) of the compounds of the presentinvention can be tested in a variety of ways using commerciallyavailable materials, reagents known in the literature or readilyprepared, by employing routine methods and procedures either known tothose skilled in the art, or which will be apparent to the skilledartisan in light of the teachings herein. Theses methods and procedurescan be obtained from the relevant scientific literature or from standardtextbooks in the field. The following descriptions of assays aredesigned to illustrate, but not to limit, general procedures forevaluating the activities of compounds of the present invention.

A general description of the assays is presented below.

Preparation of Cells for Biological Assays

Cells are prepared for assays by growing cultures for the requisiteperiod of time (e.g., up to 2 weeks). Frozen cells are thawed, and thentransferred into growth media. If necessary, the cells can be gentlycentrifuged and then resuspended in growth media. When the cells reachedthe necessary confluence (e.g., ˜95%), the cells are passaged and usedfor various biological assays, such as those described herein below.

β-Arrestin Agonist Assay

The assays can be performed using proper detection reagents eitherprepared using routine methods known in the art or commerciallyavailable (e.g., PathHunter® β-Arrestin Detecting Kit (DiscoveR_(x))).Cells are grown to the necessary confluence and then detached. The cellsare then centrifuged, washed, resuspended, and seeded into a container(e.g., 384-well plate). The cells are incubated (e.g., at 37° C., 5%CO₂) for the appropriate period of time (e.g., 24 hours), before variouscompounds (e.g., a compound of the invention or a control compound) areadded to the cells. After incubation of the cells with the compounds,detection reagents (e.g., a buffer containing Emerald II: Galactor-Staras provided DiscoveR_(x)) are added to the cells. The read-out (e.g.,luminescence, or fluorescence) is detected using standard equipment.

β-Arrestin Antagonist Assay

The assays can be conducted in the same manner as the β-arrestin agonistassay, except that before addition of the detection reagents, a D2receptor agonist (e.g., Quinpirole) is added to the cells. The detectionreagents are then added, and the read-out is detected.

Gi/cAMP Agonist Assay

The assays can be performed using proper detection reagents eitherprepared using routine methods known in the art or commerciallyavailable (e.g., PE Lance Ultra cAMP kit (TRF0263)). Cells are grown tothe necessary confluence and then detached. The cells are thencentrifuged, washed, resuspended, and seeded into a container (e.g.,384-well plate). The cells are incubated (e.g., at 37° C., 5% CO₂) forthe appropriate period of time (e.g., 24 hours), before variouscompounds (e.g., a compound of the invention or a control compound) areadded to the cells. Afterwards, cAMP inducing agents (e.g., Forskolin)are added to and incubated with the cells before detection reagents(e.g., a cAMP antibody, such as ULight-anti-cAMP solution) are added tothe cells. Read-out (e.g., luminescence, or fluorescence) is detectedusing standard equipment.

Gi/cAMP Antagonist Assay

The assays can be conducted in the same manner as the Gi/cAMP agonistassay, except that before addition of the detection reagents, a D2receptor agonist (e.g., Quinpirole) is added to the cells. The detectionreagents are then added, and the read-out is detected.

Pharmacokinetic Studies on Mice Brains

Test animals are administered (e.g., intraperitoneally, intravenously,orally) with a dose of test compounds (e.g., compounds of theinvention). Blood samples are collected and plasma is harvested from theblood. Brain tissues are also isolated and homogenized. Concentrationsof the test compounds administered in the plasma and brain samples aredetermined using routine analytic methods, such as LC-MS/MS.

Positron Emission Tomography Studies on Rodents

Non-radiolabeled test compounds (e.g., vehicle, compounds of theinvention, control compounds) are administered to the test animal,followed by administration of a radiotracer (e.g., carbon 11-labeledraclopride ([¹¹C]RAC), which can be synthesized from the O-desmethyl RACprecursor and [11C] methyl iodide and subsequently purified byhigh-performance liquid chromatography as previously described (Farde L,et al. (1985) PNAS, USA 82(11):3863-3867)). Positron emission tomography(PET) and skeletal computed tomography (CT) data are collected usingstandard equipment, such as a GammaMedica Triumph trimodal PET/SPECT/CTscanner (Quebec, Canada) or a Concorde Microsystems R4 microPET scanner(Knoxville, Tenn., USA). Routine data processing is employed, includingsubtraction of random coincidences collected in a delayed time window,and reconstruction of scatter-corrected sinograms using a knownalgorithm (e.g., 3-dimensional iterative maximum likelihood expectationmaximization (3D-MLEM) algorithm). Regions of Interest (ROIs) are drawnon reconstructed images estimating peak [¹¹C]RAC uptake in striata(averaged between left and right hemispheres) and cerebellum asreference region for non-displaceable (ND) tracer uptake. ROIdimensions, placement and striatal D2/D3 binding potential (BP_(ND)) areevaluated by graphical analysis (e.g., using Logan distribution volumeratio (DVR) linearization as previously described (BP_(ND).=DVR-1;Alexoff D, et al. (2002) JNucMed 44(5): 815-822; Logan J, et al. (1996)JCerebral Blood Flow and Metabolism 16(5):843-840)).

Amphetamine Induced Hyperactivity Studies

Amphetamine-induced hyperactivity (AIH) can be examined using routinebehavior methods, such as in open-field chambers. Activity is detectedby various methods, such as infrared beam. Daily sessions are binned forstatistical analysis. AIH can be run over various time frames, accordingto the need of the study, such as as follows:

Day 1: test animals are acclimated to the injection procedure byinjecting prior to being placed in the chambers. Test animals are thenplaced into the open-field a certain time period (e.g., 20 min) and thenremoved for a saline injection. Test animals are placed back into theopen-field for an additional period of time (e.g., 30 min), at whichpoint the test animals are returned to their home cage.

Day 2: repeat Day 1, with the exception that the timing may be different(e.g., the second day may last for one hour (20 minutes→injection→40minutes)).

Day 3: test animals are challenged by amphetamine. Test animals arepre-treated with D2 antagonist compounds (e.g., compounds of theinvention) prior to being placed in the open field. After a certainperiod of time, test animals are removed and challenged withamphetamine, following protocols known to one skilled in the art, forexample Jones C. A, et. al. Br J Pharmacol. 2011, 164(4):1162-1194; PanJ Q, et. al. Neuropsychopharmacology. 2011, 36(7):1397-1411.

Rotarod Performance

In the test, test animals are placed on a horizontally oriented,rotating cylinder (rod) suspended above a cage floor. The test animalsnaturally try to stay on the rotating cylinder, or rotarod, and avoidfalling to the ground. Test animals are administered with variouscompounds (e.g., compounds of the invention or control compounds). Thelength of time that a given animal stays on this rotating rod is ameasure of the animal's balance, coordination, physical condition, andmotor-planning. The speed of the rotarod is mechanically driven, and canbe held constant.

Pharmaceutical Compositions

The present invention also provides a pharmaceutical compositioncomprising a compound of any formulae or independently selected from anycompounds described herein, and at least one pharmaceutically acceptableexcipient or carrier. In one embodiment, the present invention relatesto pharmaceutical composition comprising a compound of any one ofFormulae (I)-(X), or a pharmaceutically acceptable salt, stereoisomer,racemate, tautomer, polymorph, hydrate, or solvate thereof, and one ormore pharmaceutically acceptable excipients or carriers.

The term “pharmaceutical composition” is defined herein as comprising aneffective amount of at least one active substance (e.g., compounds ofthe present invention), and at least one pharmaceutically acceptablecarrier or excipient, in a form suitable for administration to asubject. In one embodiment, the pharmaceutical composition is in bulk orin unit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or salt, hydrate, solvate orisomer thereof) in a unit dose of composition is an effective amount andis varied according to the particular treatment involved. One skilled inthe art will appreciate that it is sometimes necessary to make routinevariations to the dosage depending on the age and condition of thepatient. The dosage will also depend on the route of administration. Avariety of routes are contemplated, including oral, parenteral, topical,intranasal, ophthalmic, otic, rectal, transdermal, and transmucosal, andthe like. Dosage forms for the topical or transdermal administration ofa compound of the invention include powders, sprays, ointments, pastes,creams, lotions, gels, solutions, patches and inhalants. In oneembodiment, the active compound is mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives, buffersor propellants that are required.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject (e.g., human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

The term “pharmaceutically acceptable carrier or excipient” refers to acarrier medium which does not interfere with the effectiveness of thebiological activity of the active compound(s) and which is notexcessively toxic to the host at the concentration at which it isadministered. The term includes solvents, dispersion media, coatings,isotonic agents, adsorption delaying agents, and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art (see for example”, E. W. Martin, 18^(th) Ed., 1990,Mack Publishing Co.: Easton, Pa., which is incorporated herein byreference in its entirety). In certain embodiments, the pharmaceuticallyacceptable carrier or excipient is a veterinary acceptable carrier orexcipient.

The term “therapeutically effective amount” or “effective amount”, asused herein, refers to an amount of a pharmaceutical agent to treat,ameliorate, or prevent an identified disease or condition, or to exhibita detectable therapeutic or inhibitory effect. The effect can bedetected by any assay method known in the art. The precise effectiveamount for a subject will depend upon the subject's body weight, size,and health; the nature and extent of the condition; and the therapeuticor combination of therapeutics independently selected foradministration. Therapeutically effective amounts for a given situationcan be determined by routine experimentation that is within the skilland judgment of the clinician.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, or in animal models, usuallyrats, mice, rabbits, dogs, or pigs. The animal model may also be used todetermine the appropriate concentration range and route ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Therapeutic/prophylacticefficacy and toxicity may be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., ED₅₀ (thedose therapeutically effective in 50% of the population) and LD₅₀ (thedose lethal to 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index, and it can be expressed asthe ratio, LD₅₀/ED₅₀. Pharmaceutical compositions that exhibit largetherapeutic indices are preferred. The dosage may vary within this rangedepending upon the dosage form employed, sensitivity of the patient, andthe route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The compounds may be in fine particulate form, freeze-dried as a powderformulation (see for example, CA 2837693; WO2009/017250; US20100196486), in a low hygroscopic form (see for example, U.S. Pat. Nos.7,910,589, 8,017,615, 8,399,469, 8,580,796, 8,642,760; US 20040058935),or liquid or gel formulations (see for example, US 20130209552; US20130171237; WO2012/058091).

Any suitable pharmaceutically acceptable excipient can be added to thecompositions of the invention. Excipients may be added for numerousreasons, for example to facilitate manufacture, enhance stability,control release, enhance product characteristics, enhancebioavailability, enhance patient acceptability and combinations thereof.Examples of pharmaceutically acceptable excipients include diluents,vehicles, binders, disintegrants, glidants, compression aids, colouringagents, organoleptic ingredients such as flavoring agents or sweeteners,suspending agents, dispersing agents, film formers, printing inks,lubricants, preservatives, fillers, buffers, stabilisers, or othermaterials well known to those skilled in the art. These excipients maybe used in a conventional manner, and alone or in any combination.

Exemplary binders, which may be used to help to hold the dosage formtogether, include polyvinyl pyrrolidone, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose,sugars, and combinations thereof. Disintegrants (such as croscarmellosesodium) expand when wet causing a tablet to break apart. Lubricantstypically aid in the processing of powder materials. Exemplarylubricants include calcium stearate, glycerol behenate, magnesiumstearate, mineral oil, polyethylene glycol, sodium stearylfumarate,stearic acid, talc, vegetable oil, zinc stearate, and combinationsthereof An example of a glidant is silicon dioxide.

The formulations described herein may contain a filler, such as a waterinsoluble or water soluble filler, or combinations thereof. Typicalwater insoluble fillers include silicon dioxide, titanium dioxide, talc,aluinina, starch, kaolin, polacrilin potassium, powdered cellulose,microcrystalline cellulose, and combinations thereof. Typicalwater-soluble fillers include water soluble sugars and sugar alcohols,preferably lactose, glucose, fructose, sucrose, mannose, dextrose,galactose, the corresponding sugar alcohols and other sugar alcohols,such as mannitol, sorbitol, xylitol, and combinations thereof.

The present invention further provides pharmaceutical compositions, asdefined above, and methods of making a pharmaceutical compositioncomprising admixing such as blending, filling, granulation andcompressing, at least one active compound, as defined above, togetherwith one or more pharmaceutically acceptable carriers or excipients, asdescribed herein. The compositions of the invention can be prepared forexample by Direct compression and wet granulation. These and othermethods are described and/or exemplified in more detail herein.

The pharmaceutical compositions can be in any form suitable foradministration via various routes, including but not limited to, oral,parenteral, topical, intranasal, ophthalmic, otic, rectal, transdermal,and transmucosal. Where the compositions are intended for parenteraladministration, they can be formulated for intravenous, intramuscular,intraperitoneal, or subcutaneous administration or for direct deliveryinto a target organ or tissue by injection, infusion or other means ofdelivery. The delivery can be by bolus injection, short term infusion orlonger term infusion and can be via passive delivery or through theutilisation of a suitable infusion pump.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile solutions which may contain asterile diluent such as water, saline solution, fixed oils, polyethyleneglycols, glycerine, propylene glycol or other synthetic solvents;anti-oxidants such as ascorbic acid or sodium bisulfite; buffers such asacetates, citrates or phosphates; bacteriostats such as benzyl alcoholor methyl parabens; co-solvents; organic solvent mixtures; chelatingagents such as ethylenediaminetetraacetic acid; agents for theadjustment of tonicity such as sodium chloride or dextrose; cyclodextrincomplexation agents; emulsifying agents (for forming and stabilizingemulsion formulations); liposome components for forming liposomes;gellable polymers for forming polymeric gels; lyophilisationprotectants; and combinations of agents for, inter alia, stabilising theactive ingredient in a soluble form and rendering the formulationisotonic with the blood of the intended recipient. Pharmaceuticalformulations for parenteral administration may also take the form ofaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents (R. G. Strickly, Solubilizing Excipients inoral and injectable formulations, Pharmaceutical Research, Vol 21(2)2004, p 201-230). Pharmaceutical formulations for parenteraladministration may also be provided in finely divided sterile powderform for making up extemporaneously with sterile water for injection.

A drug molecule that is ionizable can be solubilized to the desiredconcentration by pH adjustment if the drug's pKa is sufficiently awayfrom the formulation pH value. The acceptable range is pH 2-12 forintravenous and intramuscular administration, but subcutaneously therange is pH 2.7-9.0. The solution pH is controlled by either the saltform of the drug, strong acids/bases such as hydrochloric acid or sodiumhydroxide, or by solutions of buffers which include but are not limitedto buffering solutions formed from glycine, citrate, acetate, maleate,succinate, histidine, phosphate, tris(hydroxymethyl)-aminomethane(TRIS), or carbonate.

The combination of an aqueous solution and a water-soluble organicsolvent/surfactant (i.e., a cosolvent) is often used in injectableformulations. The water-soluble organic solvents and surfactants used ininjectable formulations include but are not limited to propylene glycol,ethanol, polyethylene glycol 300, polyethylene glycol 400, glycerin,dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP; Pharmasolve),dimethylsulphoxide (DMSO), Solutol HS 15, Cremophor EL, Cremophor RH 60,and polysorbate 80. Such formulations can usually be, but are notalways, diluted prior to injection.

Propylene glycol, PEG 300, ethanol, Cremophor EL, Cremophor RH 60, andpolysorbate 80 are the entirely organic water-miscible solvents andsurfactants used in commercially available injectable formulations andcan be used in combinations with each other. The resulting organicformulations are usually diluted at least 2-fold prior to IV bolus or IVinfusion.

Alternatively increased water solubility can be achieved throughmolecular complexation with cyclodextrins.

Liposomes are closed spherical vesicles composed of outer lipid bilayermembranes and an inner aqueous core and with an overall diameter of <100m. Depending on the level of hydrophobicity, moderately hydrophobicdrugs can be solubilized by liposomes if the drug becomes encapsulatedor intercalated within the liposome. Hydrophobic drugs can also besolubilized by liposomes if the drug molecule becomes an integral partof the lipid bilayer membrane, and in this case, the hydrophobic drug isdissolved in the lipid portion of the lipid bilayer. A typical liposomeformulation contains water with phospholipid at 5-20 mg/ml, anisotonicifier, a pH 5-8 buffer, and optionally cholesterol.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules, vials and disposable syringes, and may bestored in a freeze-dried (lyophilised) condition requiring only theaddition of the sterile liquid carrier, for example water forinjections, immediately prior to use.

The pharmaceutical formulation can be prepared by lyophilising acompound of the invention or acid addition salt thereof. Lyophilisationrefers to the procedure of freeze-drying a composition. Freeze-dryingand lyophilisation are therefore used herein as synonyms. A typicalprocess is to solubilise the compound and the resulting formulation isclarified, sterile filtered and aseptically transferred to containersappropriate for lyophilisation (e.g., vials). In the case of vials, theyare partially stoppered with lyo-stoppers. The formulation can be cooledto freezing and subjected to lyophilisation under standard conditionsand then hermetically capped forming a stable, dry lyophile formulation.The composition will typically have a low residual water content, e.g.,less than 5%, e.g., less than 1% by weight based on weight of thelyophile.

The lyophilisation formulation may contain other excipients for example,thickening agents, dispersing agents, buffers, antioxidants,preservatives, and tonicity adjusters. Typical buffers includephosphate, acetate, citrate and glycine. Examples of antioxidantsinclude ascorbic acid, sodium bisulphite, sodium metabisulphite,monothioglycerol, thiourea, butylated hydroxytoluene, butylated hydroxylanisole, and ethylenediaminetetraacetic acid salts. Preservatives mayinclude benzoic acid and its salts, sorbic acid and its salts, alkylesters of para-hydroxybenzoic acid, phenol, chlorobutanol, benzylalcohol, thimerosal, benzalkonium chloride and cetylpyridinium chloride.The buffers mentioned previously, as well as dextrose and sodiumchloride, can be used for tonicity adjustment if necessary.

Bulking agents are generally used in lyophilisation technology forfacilitating the process and/or providing bulk and/or mechanicalintegrity to the lyophilized cake. Bulking agent means a freely watersoluble, solid particulate diluent that when co-lyophilised with thecompound or salt thereof, provides a physically stable lyophilized cake,a more optimal freeze-drying process and rapid and completereconstitution. The bulking agent may also be utilised to make thesolution isotonic.

The water-soluble bulking agent can be any of the pharmaceuticallyacceptable inert solid materials typically used for lyophilisation. Suchbulking agents include, for example, sugars such as glucose, maltose,sucrose, and lactose; polyalcohols such as sorbitol or mannitol; aminoacids such as glycine; polymers such as polyvinylpyrrolidine; andpolysaccharides such as dextran.

The ratio of the weight of the bulking agent to the weight of activecompound is typically within the range from about 1 to about 5, forexample of about 1 to about 3, e.g., in the range of about 1 to 2.

Alternatively they can be provided in a solution form which may beconcentrated and sealed in a suitable vial. Sterilisation of dosageforms may be via filtration or by autoclaving of the vials and theircontents at appropriate stages of the formulation process. The suppliedformulation may require further dilution or preparation before deliveryfor example dilution into suitable sterile infusion packs.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets.

In one preferred embodiment of the invention, the pharmaceuticalcomposition is in a form suitable for intravenous administration, forexample by injection or infusion. In another preferred embodiment, thepharmaceutical composition is in a form suitable for subcutaneous (s.c.)administration.

The compounds may be in the form of a solid or solution, or modified soas to be suitable for oral administration (see for example, U.S. Pat.Nos. 7,655,798, 8,093,387, 8,529,949; US 20020193438, WO2006/097344).Suitable formulated may also include wet granulation pharmaceuticalcompositions (see for example, US 20070154544; WO2007/081366), inclusioncomplexes, for example with cyclodextrin (see for example, U.S. Pat.Nos. 7,115,587, 7,550,445; WO2004/017897), formulated with microspheres(see for example, US 20090043898; WO2009/00169) or formulated as a patchfor transdermal delivery (see for example, US 20130171237; US20130209552; WO2012/058091). Compounds of the present invention may alsobe formulated to have extended-release profiles, see for example, U.S.Pat. Nos. 8,338,427, 8,338,428; WO2005/016262, WO2013/133448).

Pharmaceutical compositions containing a compound of the invention canbe formulated in accordance with known techniques, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping, or lyophilizing processes, seefor example, Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., USA. Pharmaceutical compositions may be formulatedin a conventional manner using one or more pharmaceutically acceptablecarriers comprising excipients and/or auxiliaries that facilitateprocessing of the active compounds into preparations that can be usedpharmaceutically. Of course, the appropriate formulation is dependentupon the route of administration chosen.

Pharmaceutical dosage forms suitable for oral administration includetablets, capsules, caplets, pills, lozenges, syrups, solutions, powders,granules, elixirs and suspensions, sublingual tablets, wafers or patchesand buccal patches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, e.g., lactose, sucrose, sorbitol or mannitol; and/or anon-sugar derived diluent such as sodium carbonate, calcium phosphate,calcium carbonate, or a cellulose or derivative thereof such as methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starchessuch as corn starch. Tablets may also contain such standard ingredientsas binding and granulating agents such as polyvinylpyrrolidone,disintegrants (e.g., swellable crosslinked polymers such as crosslinkedcarboxymethylcellulose), lubricating agents (e.g., stearates),preservatives (e.g., parabens), antioxidants (e.g., BHT), bufferingagents (for example phosphate or citrate buffers), and effervescentagents such as citrate/bicarbonate mixtures. Such excipients are wellknown and do not need to be discussed in detail here.

Capsule formulations may be of the hard gelatin or soft gelatin varietyand can contain the active component in solid, semi-solid, or liquidform. Gelatin capsules can be formed from animal gelatin or synthetic orplant derived equivalents thereof.

The solid dosage forms (tablets, capsules etc.) can be coated orun-coated, but typically have a coating, for example a protective filmcoating (e.g., a wax or varnish) or a release controlling coating. Thecoating (e.g., a Eudragit™ type polymer) can be designed to release theactive component at a desired location within the gastro-intestinaltract. Thus, the coating can be independently selected so as to degradeunder certain pH conditions within the gastrointestinal tract, therebyselectively release the compound in the stomach or in the ileum orduodenum. Alternatively or additionally, the coating can be used as ataste masking agent to mask unpleasant tastes such as bitter tastingdrugs. The coating may contain sugar or other agents that assist inmasking unpleasant tastes.

Instead of, or in addition to, a coating, the drug can be presented in asolid matrix comprising a release controlling agent, for example arelease delaying agent which may be adapted to selectively release thecompound under conditions of varying acidity or alkalinity in thegastrointestinal tract. Alternatively, the matrix material or releaseretarding coating can take the form of an erodible polymer (e.g., amaleic anhydride polymer) which is substantially continuously eroded asthe dosage form passes through the gastrointestinal tract. As a furtheralternative, the active compound can be formulated in a delivery systemthat provides osmotic control of the release of the compound. Osmoticrelease and other delayed release or sustained release formulations maybe prepared in accordance with methods well known to those skilled inthe art.

Compositions for topical use include ointments, creams, sprays, patches,gels, liquid drops and inserts (for example intraocular inserts). Suchcompositions can be formulated in accordance with known methods.

Further examples of topical compositions include dressings such asbandages and adhesive plasters impregnated with active ingredients andoptionally one or more excipients or diluents. Carriers which may beused include e.g., polyhydric alcohols such as polyethylene glycols,propylene glycol or glycerol. Suitable excipients are those known in theart to be appropriate.

Examples of formulations for rectal or intra-vaginal administrationinclude pessaries and suppositories which may be, for example, formedfrom a shaped mouldable or waxy material containing the active compound.Thus, unit-dose suppositories or pessaries may be prepared by admixtureof the active ingredient with one or more conventional solid carriers,for example coca butter, and shaping the resulting mixture. Furtherexamples of mouldable waxy materials include polymers such as highmolecular weight polyalkylene glycols, e.g., high molecular weightpolyethylene glycols. Alternatively, in the case of vaginaladministration, the formulation may be presented as a tampon impregnatedwith the active ingredients and optionally one or more excipients ordiluents. Other formulations suitable for rectal and vaginaladministration include creams, gels, foams, pastes and sprays.

Compositions for administration by inhalation may take the form ofinhalable powder compositions or liquid or powder sprays, and can beadministrated in standard form using powder inhaler devices or aerosoldispensing devices. Such devices are well known. For administration byinhalation, the powdered formulations typically comprise the activecompound together with an inert solid powdered diluent such as lactose.The compounds are delivered in the form of an aerosol spray frompressured container or dispenser, which contains a suitable propellant,e.g., a gas such as carbon dioxide, or a nebulizer.

For transmucosal or transdermal administration, penetrants appropriateto the barrier to be permeated are used in the formulation. Suchpenetrants are generally known in the art, and include, for example, fortransmucosal administration, detergents, bile salts, and fusidic acidderivatives. Transmucosal administration can be accomplished through theuse of nasal sprays or suppositories. For transdermal administration,the active compounds are formulated into ointments, salves, gels, orcreams as generally known in the art.

It is advantageous to formulate oral or parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the subject to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the uniquecharacteristics of the active compound and the particular therapeuticeffect to be achieved.

The pharmaceutical formulations can be included in a container, pack, ordispenser together with instructions for administration. Thepharmaceutical formulations may be presented to a patient in “patientpacks” containing an entire course of treatment in a single package,usually a blister pack. Patient packs have an advantage over traditionalprescriptions, where a pharmacist divides a patient's supply of apharmaceutical from a bulk supply, in that the patient always has accessto the package insert contained in the patient pack, normally missing inpatient prescriptions. The inclusion of a package insert has been shownto improve patient compliance with the physician's instructions.

The invention also provides a pharmaceutical composition comprising oneor more compounds of the present invention and a pharmaceuticallyacceptable carrier or excipient, in combination with anotherpharmaceutically active substance independently selected from a lithiumcompound independently selected from lithium carbonate, lithium citrate,lithium orotate, lithium bromide or lithium chloride; valproate; aserotonin reuptake inhibitor independently selected from fluoxetine,venlafaxine, citalopram, paroxetine, sertraline, indalpine, zimelidine,dapoxetine, fluvoxamine, tianeptine, duloxetine or escitalopram;chlorpromazine, droperidol, fluphenazine, haloperidol, loxapine,molindone, perphenazine, pimozide, prochlorperazine, thiothixene,thioridazine, trifluoperazine, levomepromazine, aripiprazole, asenapine,clozapine, iloperidone, lurasidone, olanzapine, paliperidone,quetiapine, risperidone, ziprasidone, amisulpride, blonanserin,clotiapine, mosapramine, perospirone, sertindole, sulpiride; caffeine, acaffeine derivative, nicotine, a nicotine derivative, phencyclidine,quinpirole, salvinorin a, apomorphine, bromocriptine, cabergoline,ciladopa, dihydrexidine, dinapsoline, doxanthrine, epicriptine,lisuride, pergolide, piribedil, pramipexole, propylnorapomorphine,quinagolide, ropinirole, rotigotine, roxindole, sumanirole; othercompounds with interact with dopamine D2 receptor independently selectedfrom amisulpride, nemomapride, nemoxipride, eticlopride, reclopride,talipexole, roxindole, bifeprunox, aplindore, mesoridazine, haloperidol,thixathene, flupenthixol, butyrophenone, perclamol [(−)3-PPP],saritozan, olanzapine, dopanmine, quinpirole, bromocriptine;anti-depressants independently selected from agomelatine, amitriptyline,amoxapine, clomipramine, desipramine, dosulepine hydrochloride,doxepine, imipramine, maprotiline, a mixture of nortriptyline andfluphénazine, opipramol, quinupramine, trimipramine, a mixture ofmélitracène and flupentixol, pranipexole.

The invention also provides a kit comprising (i) one or more compoundsof the present invention, (ii) an additional compound independentlyselected from a lithium compound independently selected from lithiumcarbonate, lithium citrate, lithium orotate, lithium bromide or lithiumchloride; valproate; a serotonin reuptake inhibitor independentlyselected from fluoxetine, venlafaxine, citalopram, paroxetine,sertraline, indalpine, zimelidine, dapoxetine, fluvoxamine, tianeptine,duloxetine or escitalopram; Chlorpromazine, Droperidol, Fluphenazine,Haloperidol, Loxapine, Molindone, Perphenazine, Pimozide,Prochlorperazine, Thiothixene, Thioridazine, Trifluoperazine,Levomepromazine, Aripiprazole, Asenapine, Clozapine, Iloperidone,Lurasidone, Olanzapine, Paliperidone, Quetiapine, Risperidone,Ziprasidone, Amisulpride, Blonanserin, Clotiapine, Mosapramine,Perospirone, Sertindole, Sulpiride; caffeine, a caffeine derivative,nicotine, a nicotine derivative, Phencyclidine, Quinpirole, SalvinorinA, Apomorphine, Bromocriptine, Cabergoline, Ciladopa, Dihydrexidine,Dinapsoline, Doxanthrine, Epicriptine, Lisuride, Pergolide, Piribedil,Pramipexole, Propylnorapomorphine, Quinagolide, Ropinirole, Rotigotine,Roxindole, Sumanirole; other compounds with interact with dopamine D2receptor independently selected from Amisulpride, nemomapride,nemoxipride, eticlopride, reclopride, talipexole, roxindole, bifeprunox,aplindore, mesoridazine, haloperidol, thixathene, flupenthixol,butyrophenone, perclamol [(−)3-PPP], saritozan, olanzapine, dopanmine,quinpirole, bromocriptine; other anti-depressants independently selectedfrom Agomelatine, amitriptyline, amoxapine, clomipramine, desipramine,dosulepine hydrochloride, doxepine, imipramine, maprotiline, a mixtureof nortriptyline and fluphénazine, opipramol, quinupramine,trimipramine, a mixture of melitracene and flupentixol, pranipexole, and(iii) instructions for administration of (i) and (ii). The associationof the two or more compounds/agents in a combination may be physical ornon-physical. Examples of physically associated combinedcompounds/agents include: compositions (e.g., unitary formulations)comprising the two or more compounds/agents in a mixture (for examplewithin the same unit dose); compositions comprising material in whichthe two or more compounds/agents are chemically/physicochemically linked(for example by crosslinking, molecular agglomeration or binding to acommon vehicle moiety); compositions comprising material in which thetwo or more compounds/agents are chemically/physicochemicallyco-packaged (for example, disposed on or within lipid vesicles,particles (e.g., micro- or nanoparticles) or emulsion droplets);pharmaceutical kits, pharmaceutical packs or patient packs in which thetwo or more compounds/agents are co-packaged or co-presented (e.g., aspart of an array of unit doses);

Examples of non-physically associated combined compounds/agents include:material (e.g., a non-unitary formulation) comprising at least one ofthe two or more compounds/agents together with instructions for theextemporaneous association of the at least one compound to form aphysical association of the two or more compounds/agents; material(e.g., a non-unitary formulation) comprising at least one of the two ormore compounds/agents together with instructions for combination therapywith the two or more compounds/agents; material comprising at least oneof the two or more compounds/agents together with instructions foradministration to a patient population in which the other(s) of the twoor more compounds/agents have been (or are being) administered; materialcomprising at least one of the two or more compounds/agents in an amountor in a form which is specifically adapted for use in combination withthe other(s) of the two or more compounds/agents.

As used herein, the term “pharmaceutical pack” defines an array of oneor more unit doses of a pharmaceutical composition, optionally containedwithin common outer packaging. In pharmaceutical packs comprising acombination of two or more compounds/agents, the individualcompounds/agents may be unitary or non-unitary formulations. The unitdose(s) may be contained within a blister pack. The pharmaceutical packmay optionally further comprise instructions for use.

As used herein, the term “pharmaceutical kit” or “kit” defines an arrayof one or more unit doses of a pharmaceutical composition together withdosing means (e.g., measuring device) and/or delivery means (e.g.,inhaler or syringe), optionally all contained within common outerpackaging. In pharmaceutical kits comprising a combination of two ormore compounds/agents, the individual compounds/agents may be unitary ornon-unitary formulations. The unit dose(s) may be contained within ablister pack. The pharmaceutical kit may optionally further compriseinstructions for use.

As used herein, the term “patient pack” defines a package, prescribed toa patient, which contains pharmaceutical compositions for the wholecourse of treatment. Patient packs usually contain one or more blisterpack(s). Patient packs have an advantage over traditional prescriptions,where a pharmacist divides a patient's supply of a pharmaceutical from abulk supply, in that the patient always has access to the package insertcontained in the patient pack, normally missing in patientprescriptions. The inclusion of a package insert has been shown toimprove patient compliance with the physician's instructions.

The term “stable” as used herein, refers to dosage form which isphysically, or polymorphically stable. The dosage form according topresent invention may remain physically stable, that is there are nosubstantial changes with respect to physical attributes like colour etc.The dosage form according to present invention may remainpolymorphically stable that is the polymorph (crystalline or amorphous)in the dosage form does not rearranges into another form upon storage.

Method of Use

The term “patient” refers to a warm-blood animal, preferably a humanbeing, i.e., a subject of both genders and at any stage development(i.e., neonate, infant, juvenile, adolescent, adult). The invention isparticularly directed to adolescents and adults. Some embodiments, inparticular concerning regulation of galactorrhea, are specificallydirected to female.

As used herein, “treating” or “treat” describes the management and careof a patient for the purpose of combating a disease, condition, ordisorder and includes the administration of a compound of the presentinvention, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, to alleviate the symptoms or complicationsof a disease, condition or disorder, or to eliminate the disease,condition or disorder.

As used herein, “preventing” or “prevent” describes reducing oreliminating the onset of the symptoms or complications of the disease,condition or disorder.

As used herein, the term “alleviate” is meant to describe a process bywhich the severity of a sign or symptom of a disorder is decreased.Importantly, a sign or symptom can be alleviated without beingeliminated. In a preferred embodiment, the administration ofpharmaceutical compositions of the invention leads to the elimination ofa sign or symptom, however, elimination is not required. Effectivedosages are expected to decrease the severity of a sign or symptom. Forinstance, a sign or symptom of a disorder such as cancer, which canoccur in multiple locations, is alleviated if the severity of the canceris decreased within at least one of multiple locations.

As used herein, the term “modulation”, as applied to the activity of thedopamine activity at D2 receptors, is intended to define a change in thelevel of biological activity of the dopaminergic activity. Thus,modulation encompasses physiological changes which effect an increase ordecrease in the dopaminergic activity. In the latter case, themodulation may be described as “inhibition”. The modulation may arisedirectly or indirectly, and may be mediated by any mechanism and at anyphysiological level, including for example at the level of geneexpression (including for example transcription, translation and/orpost-translational modification), at the level of expression of genesencoding regulatory elements which act directly or indirectly on thelevels of dopaminergic activity. Thus, modulation may implyelevated/suppressed expression or over- or under-expression ofdopaminergic activity, including gene amplification (i.e., multiple genecopies) and/or increased or decreased expression by a transcriptionaleffect, as well as hyper- (or hypo-) activity and (de)activation ofdopaminergic activity (including (de)activation) by mutation(s). Theterms “modulated”, “modulating” and “modulate” are to be interpretedaccordingly.

The present invention provides a method of modulating D2 receptoractivity by administering one or more compounds of the present inventionto a subject. The active compound will be administered to a subject inneed thereof (for example a human or animal patient) in an amountsufficient to achieve the desired therapeutic effect. In one embodiment,the present invention relates to a method of modulating D2 receptoractivity, comprising administering a compound of any one of Formulae(I)-(X), or a pharmaceutically acceptable salt, stereoisomer, racemate,tautomer, polymorph, hydrate, or solvate thereof.

The present invention also provides use of one or more compounds of thepresent invention as a β-arrestin biased D2 receptor agonist orantagonist. The present invention also provides use of one or morecompounds of the present invention as a biased cAMP agonist orantagonist. In one embodiment, the present invention relates to the useof a compound of any one of Formulae (I)-(X), or a pharmaceuticallyacceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate,or solvate thereof, for modulating the β-arrestin pathway downstream ofthe D2 receptor (β-arrestin biased) as an agonist or antagonist. Inanother embodiment, the present invention relates to the use of acompound of any one of Formulae (I)-(X), or a pharmaceuticallyacceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate,or solvate thereof, for modulating the Gi/cAMP pathway downstream of theD2 receptor (Gi/cAMP biased) as an agonist or antagonist.

The present invention provides a method of treating or preventing adisease or disorder, comprising administering a compound of theinvention, wherein modulation of the D2 receptors (e.g., β-arrestin orGi/cAMP) plays a role in the disease or disorder (iniation, development,etc.). In one embodiment, the disease or disorder is a nervous systemdisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role. In one embodiment, the presentinvention relates to a method of treating or preventing a disease ordisorder in which modulation of D2 receptors plays a role, comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of any one of Formulae (I)-(X), or apharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof, in combination with apharmaceutically acceptable excipient or carrier. The nervous systemdisorder is independently selected from an anxiety disorder (e.g.,phobias, generalized anxiety disorder, social anxiety disorder, panicdisorder, agoraphobia, obsessive-compulsive disorder, and post-traumaticstress disorder), a dissociative disorder (e.g., dissociative amnesia,dissociative fugue, dissociative identity (multiple personality)disorder, and depersonalization disorder), a mood disorder (e.g.,depression, dysthymia, bipolar disorder, mania, hypomania, andCyclothymic Disorder), an eating disorder (e.g., anorexia nervosa,bulimia nervosa, exercise bulimia, and binge eating disorder), a sleepdisorder (insomnia, hypersomnia, narcolepsy, nightmare disorder, sleepterror disorder, and sleepwalking), a developmental disorder (e.g.,autism spectrum disorders, oppositional defiant disorder and conductdisorder, and attention deficit hyperactivity disorder), a somatoformdisorder (e.g., body dysmorphic disorder, conversion disorder,hypochondriasis disorder, pain disorder, and somatization disorder), apersonality disorder (e.g., antisocial personality disorder, borderlinepersonality disorder, narcissistic personality disorder), a psychiatricsyndrome (e.g., Capgras syndrome, De Clerambault syndrome, Othellosyndrome, Ganser syndrome, Cotard delusion, and Ekbom syndrome, andadditional disorders such as the Couvade syndrome and Geschwindsyndrome), a psychotic disorder (e.g., brief psychotic disorder,delusional disorder, Schizoaffective disorder, Schizophrenia,Schizophreniform, shared psychotic disorder), substance abuse,Parkinson's disease, Huntington's disease, Alzheimer's disease,dementia, Niemann-Pick disorder, a pituitary disorder (e.g., pituitaryadenoma, and a pituitary tumor such as prolactinoma)), Tourette'ssyndrome, Tourette-like disorders, and restless leg syndrome.

In another aspect, the present invention relates to the use of acompound of any one of Formulae (I)-(X), or a pharmaceuticallyacceptable salt, stereoisomer, racemate, tautomer, polymorph, hydrate,or solvate thereof, for the treatment or prevention of a disease ordisorder in which modulation of D2 receptors plays a role.

Another aspect of the present invention relates to the use of a compoundof any one of Formulae (I)-(X), or a pharmaceutically acceptable salt,stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, in the manufacture of a medicament for the treatment orprevention of a disease or disorder in which modulation of D2 receptorsplays a role.

In one embodiment, the present invention provides a method of treatingor preventing a disease or disorder in which modulation of D2 receptors(e.g., β-arrestin or Gi/cAMP) plays a role, independently selected fromobsessive-compulsive disorder, post-traumatic stress disorder,depression, bipolar disorder, mania, hypomania, autism spectrumdisorders, attention deficit hyperactivity disorder, delusionaldisorder, Schizoaffective disorder, Schizophrenia, Schizophreniform,substance abuse, Parkinson's disease, Huntington's disease, Alzheimer'sdisease, dementia, Niemann-Pick disorder, a pituitary disorder,Tourette's syndrome, Tourette-like disorders, and restless leg syndrome.

In another embodiment, the disease or disorder is a non-nervous systemdisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role, such as cardiovascular diseases ordisorders (e.g., hypertension), renal diseases or disorders (e.g., adisease or disorder associated with diuresis and natriuresis), andendocrine diseases or disorders (e.g., galactorrhea), and immunologicaldiseases or disorders.

The present invention also provides a method of treating or preventing adisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role (e.g., the diseases and disordersdescribed above), comprising administering a compound of the inventionand an additional therapeutic agent. In one embodiment, the additionaltherapeutic agent is lithium carbonate, lithium citrate, lithiumorotate, lithium bromide or lithium chloride. In another embodiment, theadditional therapeutic agent is valproate. In another embodiment, theadditional therapeutic agent is caffeine (e.g., as to Parkinsons), acaffeine derivative (e.g., as to Parkinsons), nicotine (e.g., as toParkinsons), a nicotine derivative (e.g., as to Parkinsons),Phencyclidine (a.k.a. PCP), Quinpirole, Salvinorin A (chief activeconstituent of the herb salvia divinorum), Apomorphine (Apokyn) (e.g.,as to Parkinson's disease, restless leg syndrome), Bromocriptine(Parlodel) (e.g., as to Parkinson's disease, restless leg syndrome),Cabergoline (Dostinex) (e.g., as to Parkinson's disease, restless legsyndrome), Ciladopa (e.g., as to Parkinson's disease, restless legsyndrome), Dihydrexidine (e.g., as to Parkinson's disease, restless legsyndrome), Dinapsoline (e.g., as to Parkinson's disease, restless legsyndrome), Doxanthrine (e.g., as to Parkinson's disease, restless legsyndrome), Epicriptine (e.g., as to Parkinson's disease, restless legsyndrome), Lisuride (e.g., as to Parkinson's disease, restless legsyndrome), Pergolide (e.g., as to Parkinson's disease, restless legsyndrome), Piribedil (e.g., as to Parkinson's disease, restless legsyndrome), Pramipexole (e.g., as to Parkinson's disease, restless legsyndrome) (Mirapex and Sifrol), Propylnorapomorphine (e.g., as toParkinson's disease, restless leg syndrome), Quinagolide (Norprolac)(e.g., as to Parkinson's disease, restless leg syndrome), Ropinirole(e.g., as to Parkinson's disease, restless leg syndrome) (Requip),Rotigotine (e.g., as to Parkinson's disease, restless leg syndrome)(Neupro), Roxindole (e.g., as to Parkinson's disease, restless legsyndrome), or Sumanirole (e.g., as to Parkinson's disease, restless legsyndrome).

The present invention also provides a method of treating or preventing adisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role (e.g., the diseases and disordersdescribed above), comprising administering a compound of the inventionand a serotonin reuptake inhibitor such as fluoxetine, venlafaxine,citalopram, paroxetine, sertraline, indalpine, zimelidine, dapoxetine,fluvoxamine, tianeptine, duloxetine or escitalopram (see for example,US20060154938).

The present invention also provides a method of treating or preventing adisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role (e.g., the diseases and disordersdescribed above), comprising administering a compound of the inventionalone or in combination with antipsychotics. Examples of typical (firstgeneration) antipsychotics include Chlorpromazine, Droperidol,Fluphenazine, Haloperidol, Loxapine, Molindone, Perphenazine, Pimozide,Prochlorperazine, Thiothixene, Thioridazine, Trifluoperazine,Levomepromazine. Examples of atypical (second generation) antipsychoticsinclude Aripiprazole, Asenapine, Clozapine, Iloperidone, Lurasidone,Olanzapine, Paliperidone, Quetiapine, Risperidone, Ziprasidone,Amisulpride, Blonanserin, Clotiapine, Mosapramine, Perospirone,Sertindole, Sulpiride. Other compounds which can be used in combinationwith the compounds of the invention are for example compounds thatinteract with dopamine D2 receptor independently selected fromamisulpride, nemomapride, nemoxipride, eticlopride, reclopride,talipexole, roxindole, bifeprunox, aplindore, mesoridazine, haloperidol,thixathene, flupenthixol, butyrophenone, perclamol [(−)3-PPP],saritozan, olanzapine, dopanmine, quinpirole, bromocriptine; otheranti-depressants independently selected from Agomelatine, amitriptyline,amoxapine, clomipramine, desipramine, dosulepine hydrochloride,doxepine, imipramine, maprotiline, a mixture of nortriptyline andfluphénazine, opipramol, quinupramine, trimipramine, a mixture ofmelitracene and flupentixol, pranipexole.

The compounds are generally administered to a subject in need of suchadministration, for example, a human or animal patient, preferably ahuman.

The compounds will typically be administered in amounts that aretherapeutically or prophylactically useful and which generally arenon-toxic. However, in certain situations (for example in the case oflife threatening diseases), the benefits of administering a compound ofthe formula (I) may outweigh the disadvantages of any toxic effects orside effects, in which case it may be considered desirable to administercompounds in amounts that are associated with a degree of toxicity. Thequantity of compound administered and the type of composition used willbe commensurate with the nature of the disease or physiologicalcondition being treated and will be at the discretion of the physician.

The compounds may be administered over a prolonged term to maintainbeneficial therapeutic effects or may be administered for a short periodonly. Alternatively they may be administered in a pulsatile orcontinuous manner.

The compounds as defined herein can be administered as the soletherapeutic agent or they can be administered in combination therapywith one of more other compounds for treatment of a particular diseasestate, for example, a nervous system disorder. The compounds of theinvention may also be administered in conjunction with other treatmentssuch as radiotherapy, photodynamic therapy, gene therapy, surgery andcontrolled diets.

Where the compound is administered in combination with other therapeuticagents, the compounds can be administered simultaneously orsequentially. When administered sequentially, they can be administeredat closely spaced intervals (e.g., within minutes) or at longerintervals (e.g., hours apart, or longer), the precise dosage regimenbeing commensurate with the properties of the therapeutic agent(s).

For use in combination therapy with another therapeutic agent, thecompound and other therapeutic agents can be, for example, formulatedtogether in a dosage form. In an alternative, the individual therapeuticagents may be formulated separately and presented together in the formof a kit, optionally with instructions for their use.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of the invention may be varied so as to obtain an amount ofthe active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The independently selected dosage level will depend upon a variety offactors including the activity of the particular compound of the presentinvention employed, the route of administration, the time ofadministration, the rate of excretion of the particular compound beingemployed, the duration of the treatment, other drugs, compounds and/ormaterials used in combination with the particular compound employed, theage, sex, weight, condition, general health and prior medical history ofthe patient being treated, and like factors well known in the medicalarts.

A person skilled in the art would know through his or her common generalknowledge the use of suitable dosing regimes and combination therapies.The regimen of administration can affect what constitutes an effectiveamount. The compound of the invention can be administered to the subjecteither prior to or after the onset of a dopaminergic disorder. Further,several divided dosages, as well as staggered dosages, can beadministered daily or sequentially, or the dose can be continuouslyinfused, or can be a bolus injection. Further, the dosages of thecompound(s) of the invention can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical composition.

The present invention also relates to use of a compound of the inventionor a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof, or use of a pharmaceuticalcomposition of the invention, for treating treating or preventing adisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role (e.g., diseases and disordersdescribed herein). In one embodiment, the disease or disorder is anervous system disease or disorder independently selected fromobsessive-compulsive disorder, post-traumatic stress disorder,depression, bipolar disorder, mania, hypomania, autism spectrumdisorders, attention deficit hyperactivity disorder, delusionaldisorder, Schizoaffective disorder, Schizophrenia, Schizophreniform,substance abuse, Parkinson's disease, Huntington's disease, Alzheimer'sdisease, dementia, Niemann-Pick disorder, a pituitary disorder,Tourette's syndrome, Tourette-like disorders, and restless leg syndrome.In another embodiment, the disease or disorder is a non-nervous systemdisease or disorder in which modulation of D2 receptors (e.g.,β-arrestin or Gi/cAMP) plays a role, such as cardiovascular diseases ordisorders (e.g., hypertension), renal diseases or disorders (e.g., adisease or disorder associated with diuresis and natriuresis), andendocrine diseases or disorders (e.g., galactorrhea), and immunologicaldiseases or disorders.

The present invention also relates to use of a compound of theinvention, or a pharmaceutically acceptable salt, stereoisomer,racemate, tautomer, polymorph, hydrate, or solvate thereof, or use of apharmaceutical composition of the invention, in the manufacture of amedicament for the treatment or prevention of a disease or disorder inwhich modulation of D2 receptors (e.g., β-arrestin or Gi/cAMP) plays arole (e.g., diseases and disorders described herein). In one embodiment,the disease or disorder is a nervous system disease or disorderindependently selected from obsessive-compulsive disorder,post-traumatic stress disorder, depression, bipolar disorder, mania,hypomania, autism spectrum disorders, attention deficit hyperactivitydisorder, delusional disorder, Schizoaffective disorder, Schizophrenia,Schizophreniform, substance abuse, Parkinson's disease, Huntington'sdisease, Alzheimer's disease, dementia, Niemann-Pick disorder, apituitary disorder, Tourette's syndrome, Tourette-like disorders, andrestless leg syndrome. In another embodiment, the disease or disorder isa non-nervous system disease or disorder associated in which modulationof D2 receptors (e.g., β-arrestin or Gi/cAMP) plays a role, such ascardiovascular diseases or disorders (e.g., hypertension), renaldiseases or disorders (e.g., a disease or disorder associated withdiuresis and natriuresis), and endocrine diseases or disorders (e.g.,galactorrhea), and immunological diseases or disorders.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present invention areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentinvention. The examples do not limit the claimed invention. Based on thepresent disclosure the skilled artisan can identify and employ othercomponents and methodology useful for practicing the present invention.

Examples Synthesis of Intermediate-1

1-(2-bromoethoxy)-3-chlorobenzene

To a stirred solution of 3-chlorophenol (5 g, 39.06 mmol) in DMF (30 mL)under argon atmosphere were added 1,2-dibromo ethane (6.7 mL, 77.71mmol, 2 equiv) and potassium carbonate (5.4 g, 39.13 mmol, 1 equiv) atroom temperature. The reaction mixture was heated at 100° C. and stirredfor 16 h. After completion, the reaction mixture was diluted with waterand extracted with EtOAc. The combined organic extract was washed withbrine, dried over sodium sulphate, filtered and concentrated underreduced pressure. Purification using silica gel column chromatography(2% EtOAc/Hexanes as eluent) afforded 3.1 g of1-(2-bromoethoxy)-3-chlorobenzene (Yield=34%).

Synthesis of Intermediate-2

1-(2-Bromoethoxy)-2-fluorobenzene

To a stirred solution of 2-fluorophenol (0.5 g, 4.46 mmol) in aqueoussodium hydroxide solution (0.78 g, 4.46 mmol, 1 equiv, in 5 mL of water)was added 1,2-dibromo ethane (1.25 g, 6.69 mmol, 1.5 equiv) at roomtemperature. The reaction mixture was heated at 130° C. and stirred for16 h. After completion, the reaction mixture was extracted with EtOAc.The combined organic extract was washed with brine, dried over sodiumsulphate, filtered and concentrated under reduced pressure. Purificationusing silica gel column chromatography (2% EtOAc/Hexanes as eluent)afforded 0.340 g of 1-(2-bromoethoxy)-2-fluorobenzene (Yield=34.8%).

Synthesis of Intermediate-3

1-(2-Bromoethoxy)-2-(trifluoromethyl)benzene

To a stirred solution of 2-(trifluoromethyl) phenol (1 g, 6.17 mmol) inacetone (20 mL) under argon atmosphere were added potassium carbonate(0.851 g, 6.15 mmol, 1 equiv) and 1,2-dibromo ethane (1.07 mL, 12.34mmol, 2 equiv) at room temperature. The reaction mixture was heated at60° C. and stirred for 16 h. After completion, the reaction mixture wasdiluted with water and extracted with EtOAc. The combined organicextract was dried over sodium sulfate, filtered and concentrated underreduced pressure. Purification using silica gel column chromatography(2% EtOAc/Hexanes as eluent) afforded 0.40 g of1-(2-bromoethoxy)-2-(trifluoromethyl)benzene (Yield=24%).

Synthesis of Intermediate-4

1-(2-bromoethyl)pyridin-2(1H)-one

To a stirred solution of pyridin-2-ol (5 g, 52.57 mmol) in DMF (50 mL)under argon atmosphere were added cesium carbonate (17.03 g, 52.56 mmol,1.0 equiv) and 1-chloro-2-bromo ethane (15.06 g, 104.94 mmol, 2 equiv)at room temperature and stirred for 16 h. After completion, the reactionmixture was diluted with water and extracted with CH₂Cl₂. The combinedorganic extract was dried over sodium sulfate, filtered and concentratedunder reduced pressure. Purification using silica gel columnchromatography (1% MeOH/CH₂Cl₂ as eluent) afforded 1.0 g of1-(2-bromoethyl)pyridin-2(1H)-one (Yield=12%). ESI+MS: m/z 158.1([M+H]⁺).

Synthesis of Intermediate-5

7-(2-Bromoethoxy)-3,4-dihydroquinolin-2(1H)-one

To a stirred solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (1 g,6.21 mmol) in MeOH (20 mL) under argon atmosphere were added 1,2-dibromoethane (1.74 g, 9.31 mmol, 1.5 equiv) and potassium hydroxide (0.453 g,8.07 mmol, 1.3 equiv) at room temperature. The reaction mixture washeated at 65° C. and stirred for 4 h. After completion, the volatileswere removed under reduced pressure. The residue was diluted with waterand extracted with EtOAc. The combined organic extract was dried oversodium sulfate, filtered and concentrated under reduced pressure.Purification using silica gel column chromatography (1% MeOH/CH₂Cl₂ aseluent) afforded 7-(2-bromoethoxy)-3, 4-dihydroquinolin-2(1H)-one 0.27 g(Yield=16.2%). ESI+MS: m/z 267.9 ([M+H]⁺).

Intermediate-6

(2-Bromoethoxy)cyclohexane

To a stirred solution of trifluoromethane sulfonic acid silver salt(0.14 g, 0.54 mmol, 0.03 equiv) in toluene (10 mL) under argonatmosphere were added triphenyl phosphine (0.14 g, 0.54 mmol, 0.03equiv), AuCl(TPP) (0.27 g, 0.54 mmol, 0.03 equiv) and purged with argonfor 5 min in a sealed tube. To this cyclohexene (1.5 g, 18.25 mmol) and2-bromo ethanol (4.52 g, 36.45 mmol, 2 equiv) were added at roomtemperature. The reaction mixture was heated at 85° C. and stirred for24 h. After completion, the reaction mixture was diluted with diethylether and filtered. The filtrate was concentrated under reducedpressure. Purification using silica gel column chromatography (2%EtOAc/Hexanes) afforded 0.26 g of (2-bromoethoxy)cyclohexane(Yield=10%).

One skilled in the art will recognize that other compounds describedbelow were prepared in a similar manner to the procedures describedabove.

(2-Bromoethoxy)benzene

Title compound was prepared from phenol (20 g, 213 mmol) using thegeneral methodology of Int-2 and afforded 26 g of (2-bromoethoxy)benzene(Yield=61%).

1-(2-Bromoethoxy)-2-chlorobenzene

Title compound was prepared from o-cresol (5 g, 46.2 mmol) using generalmethodology of Intermediate-2 to afford 5.2 g of1-(2-bromoethoxy)-2-methylbenzene (Yield=52%).

1-(2-Bromoethoxy)-3-methylbenzene

Title compound was prepared from m-cresol (5 g, 46.2 mmol) using thegeneral methodology of Intermediate-2 to afford 5.4 g of1-(2-bromoethoxy)-3-methylbenzene (Yield=54%).

1-(2-Bromoethoxy)-4-methylbenzene

Title compound was prepared from p-cresol (5 g, 46.2 mmol) using thegeneral methodology of Intermediate-2 to afford 4 g of1-(2-bromoethoxy)-4-methylbenzene (Yield=40%).

1-(2-bromoethoxy)-2-chlorobenzene

Title compound was prepared from 2-chlorophenol (1 g, 7.78 mmol) usinggeneral methodology of Intermediate-1 to obtain 0.348 g of1-(2-bromoethoxy)-2-chlorobenzene (Yield=19%).

1-(2-Bromoethoxy)-4-chlorobenzene

Title compound was prepared from 4-chlorophenol (5 g, 39.06 mmol) usingthe general methodology of Intermediate-1 and afforded 3 g of1-(2-Bromoethoxy)-4-chlorobenzene (Yield=33%).

4-(2-Bromoethoxy)-1,2-dichlorobenzene

Title compound was prepared from 3,4-dichlorophenol (2 g, 12.27 mmol)using the general methodology of Intermediate-2. Purification usingsilica gel column chromatography (10% EtOAc/Hexanes) afforded 2 g of4-(2-bromoethoxy)-1,2-dichlorobenzene (Yield=60%).

1-(2-Bromoethoxy)-3-fluorobenzene

Title compound was prepared from 3-fluorophenol (4 g, 35.71 mmol) usingthe general methodology of Intermediate-2 and afforded 3 g of1-(2-bromoethoxy)-3-fluorobenzene (Yield=38%).

1-(2-bromoethoxy)-4-fluorobenzene

Title compound was prepared from 4-fluorophenol (4 g, 35.71-mmol) usingthe general methodology of Intermediate-2 and afforded 2.8 g of1-(2-bromoethoxy)-4-fluorobenzene (Yield=35%).

2-(2-Bromoethoxy)-1,4-difluorobenzene

Title compound was prepared from 2,6-difluorophenol (1 g, 7.69 mmol)using the general methodology of Intermediate-2 and afforded 1.1 g of2-(2-bromoethoxy)-1,4-difluorobenzene (Yield=60%).

1-(2-Bromoethoxy)-2,4-difluorobenzene

Title compound was prepared from 2,4-difluorophenol (5 g, 38.4 mmol)using the general methodology of Intermediate-2 to afford 2.5 g of2-(2-bromoethoxy)-1,4-difluorobenzene (Yield=27%).

2-(2-bromoethoxy)-1,4-difluorobenzene

Title compound was prepared from 2,5-difluorophenol (5 g, 38.4 mmol)using the general methodology of Int-2 and afforded 3.5 g of2-(2-bromoethoxy)-1,4-difluorobenzene (Yield=39%).

1-(2-bromoethoxy)-3-(trifluoromethyl)benzene

Title compound was prepared from 3-(trifluoromethyl) phenol (2 g, 12.34mmol) using general methodology of Intermediate-3 and afforded 0.74 g of1-(2-bromoethoxy)-3-(trifluoromethyl)benzene (Yield=22%).

1-(2-bromoethoxy)-4-(trifluoromethyl)benzene

Title compound was prepared from 4-(trifluoromethyl) phenol (1 g, 6.17mmol) using the general methodology of Intermediate-3 and afforded 0.3 gof 1-(2-bromoethoxy)-4-(trifluoromethyl)benzene (Yield=19%).

5-(2-bromoethoxy)-2-(trifluoromethyl)pyridine

Title compound was prepared from 6-(trifluoromethyl)pyridin-3-ol (0.5 g,3.1 mmol) using the general methodology of Intermediate-2 and afforded0.085 g 5-(2-bromoethoxy)-2-(trifluoromethyl)pyridine (Yield=10%).

3-(2-Bromoethoxy)pyridine

Title compound was prepared from pyridin-3-ol (5 g, 52.57 mmol) usingthe general methodology of Intermediate-4 and afforded 0.6 g of3-(2-bromoethoxy)pyridine (Yield=6%).

1-(2-bromoethyl)pyridin-4(1H)-one

Title compound was prepared from pyridin-4-ol (5 g, 52.5 mmol) using thegeneral methodology of Intermediate-4 and afforded 0.85 g of1-(2-bromoethyl)pyridin-4(1H)-one (Yield=8%).

1-(2-Bromoethoxy)-2-methoxybenzene

Title compound was prepared from 2-methoxyphenol (5 g, 40.3 mmol) usingthe general methodology of Intermediate-2. Purification by silica gelcolumn chromatography (5% EtOAc/Hexanes) afforded 2.85 g of1-(2-bromoethoxy)-2-methoxybenzene (Yield=30%).

1-(2-bromoethoxy)-3-methoxybenzene

Title compound was prepared from 3-methoxyphenol (5 g, 40.27 mmol) usingthe general methodology of Intermediate-2 and afforded 3.6 g of1-(2-bromoethoxy)-3-methoxybenzene (Yield=39%).

1-(2-bromoethoxy)-4-methoxybenzene

Title compound was prepared from 3-methoxyphenol (5 g, 40.27 mmol) usingthe general methodology of Int-2 and afforded 3.5 g of1-(2-bromoethoxy)-4-methoxybenzene (Yield=38%).

1-(2-bromoethoxy)-4-fluoro-2-methoxybenzene

Title compound was prepared from 4-fluoro-2-methoxyphenol (1 g, 7.04mmol) using the general methodology of Intermediate-3. Purification bysilica gel column chromatography (10% EtOAc/Hexanes) afforded 0.20 g of1-(2-bromoethoxy)-4-fluoro-2-methoxybenzene (Yield=12%).

2-(2-bromoethoxy)-4-fluoro-1-methoxybenzene

Title compound was prepared from 4-fluoro-2-methoxyphenol (1 g, 7.04mmol) using the general methodology of Intermediate-3. Purification bysilica gel column chromatography (10% EtOAc/Hexanes) afforded 0.50 g of2-(2-bromoethoxy)-4-fluoro-1-methoxybenzene (Yield=29%).

1-(2-Bromoethoxy)-2-ethylbenzene

Title compound was prepared from 2-ethylphenol (5 g, 40.9 mmol, 1 equiv)using the general methodology of Intermediate-2. Purification usingsilica gel column chromatography (2% MeOH/DCM) afforded 3.0 g of1-(2-bromoethoxy)-2-ethylbenzene (Yield=32%).

1-(2-bromoethoxy)-2-isopropylbenzene

Title compound was prepared from 2-isopropylphenol (5 g, 36.7 mmol, 1equiv) using the general methodology of Intermediate-2. Purificationusing silica gel column chromatography (5% EtOAc in Hexanes) afforded5.5 g of 1-(2-bromoethoxy)-2-isopropylbenzene (Yield=62%).

2-(2-Bromoethoxy)benzonitrile

Title compound was prepared from 2-hydroxybenzonitrile (1 g, 8.40 mmol)and 1,2-dibromoethane (3.15 g, 16.8 mmol, 2 equiv) using the generalmethodology of Intermediate-1. Purification using silica gelchromatography (2% MeOH/CH₂Cl₂) afforded 0.22 g of2-(2-bromoethoxy)benzonitrile (Yield=11%).

1-(2-bromoethoxy)-2-(trifluoromethoxy)benzene

Title compound was prepared from 2-(trifluoromethoxy)phenol (1 g, 5.6mmol) using the general methodology of Intermediate-3. Purificationusing silica gel chromatography (2% EtOAc/Hexane) afforded 1.0 g of1-(2-bromoethoxy)-2-(trifluoromethoxy)benzene (Yield=63%).

1-(2-Bromoethoxy)-4-fluoro-2-(trifluoromethyl)benzene

Title compound was prepared from 4-fluoro-2-(trifluoromethyl)phenol (2g, 11.1 mmol) using the general methodology of Intermediate-3.Purification using silica gel column chromatography (15% EtOAc inHexanes) afforded 1.6 g of1-(2-bromoethoxy)-4-fluoro-2-(trifluoromethyl)benzene (Yield=50%).

2-(2-Bromoethoxy)-4-fluoro-1-(trifluoromethyl)benzene

Title compound was prepared from 5-fluoro-2-(trifluoromethyl)phenol (1g, 5.5 mmol) using the general methodology of Intermediate-3.Purification by silica gel column chromatography (5% EtOAc/Hexanes)afforded 0.7 g of 2-(2-bromoethoxy)-4-fluoro-1-(trifluoromethyl)benzene(Yield=44%).

3-(2-Bromoethoxy)-4-(trifluoromethyl)pyridine

Title compound was prepared from3-(2-bromoethoxy)-4-(trifluoromethyl)pyridine (0.2 g, 1.22 mmol) usingthe general methodology of Intermediate-4. Purification using silica gelcolumn chromatography (10% EtOAc/Hexanes) afforded 0.11 g of3-(2-bromoethoxy)-4-(trifluoromethyl)pyridine (Yield=33%).

3-(2-bromoethoxy)-2-(trifluoromethyl)pyridine

Title compound was prepared from 2-(trifluoromethyl)pyridin-3-ol (0.5 g,3.1 mmol) using the general methodology of Intermediate-4. Purificationusing silica gel column chromatography (10% EtOAc/Hexanes) afforded 0.20g of 3-(2-bromoethoxy)-2-(trifluoromethyl)pyridine (Yield=24%).

1-(2-bromoethyl)-3-(trifluoromethyl)pyridin-2(1H)-one

Title compound was prepared from 3-(trifluoromethyl)pyridin-2-ol (0.2 g,1.22 mmol) and 1-bromo-2-chloroethane (0.52 g, 3.68 mmol, 3 equiv) usingthe general methodology of Intermediate-4. Purification using silica gelcolumn chromatography (20% EtOAc/Hexanes) afforded 0.1 g of1-(2-bromoethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (Yield=36%).

1-(2-Bromoethoxy)naphthalene

Title compound was prepared from naphthalen-1-ol (3 g, 20.81 mmol) usingthe general methodology of Intermediate-2. Purification using silica gelcolumn chromatography (7% EtOAc/Hexanes) afforded 2.5 g of1-(2-bromoethoxy) naphthalene (Yield=48%).

2-(2-Bromoethoxy)naphthalene

Title compound was prepared from naphthalen-2-ol (3 g, 20.81 mmol) usingthe general methodology of Intermediate-2. Purification using silica gelcolumn chromatography (10% EtOAc/Hexanes) afforded 2.5 g of2-(2-bromoethoxy)naphthalene (Yield=48%).

7-(2-bromoethoxy) quinolone

Title compound was prepared from quinolin-7-ol (1 g, 6.89 mmol) usingthe general methodology of Int-1 and afforded 0.21 g of7-(2-bromoethoxy) quinolone (Yield=21%).

6-(2-Bromoethoxy)isoquinoline

Title compound was prepared from isoquinolin-6-ol (0.5 g, 3.44 mmol)using the general methodology of Intermediate-4. Purification usingsilica gel column chromatography (2% MeOH/DCM) afforded 0.15 g of6-(2-bromoethoxy)isoquinoline (Yield=17%).

6-(2-Bromoethoxy)isoquinoline

Title compound was prepared from isoquinolin-6-ol (0.5 g, 3.44 mmol)using the general methodology of Intermediate-4. Purification usingsilica gel column chromatography (2% MeOH/DCM) afforded 0.15 g of6-(2-bromoethoxy)isoquinoline (Yield=17%).

6-(2-Bromoethoxy)quinolone

Title compound was prepared from quinolin-6-ol (1 g, 6.89 mmol) usingthe general methodology of Intermediate-4. Purification using silica gelcolumn chromatography (2% MeOH/DCM) afforded 0.25 g of6-(2-bromoethoxy)quinolone (Yield=14%).

5-(2-Bromoethoxy)benzo[d]thiazole

Title compound was prepared from benzo[d]thiazol-5-ol (0.10 g, 0.66mmol) using the general methodology of Intermediate-3. Purificationusing silica gel column chromatography (15% EtOAc/hexanes) afforded 0.04g of 5-(2-bromoethoxy)benzo[d]thiazole (Yield=23%).

6-(2-Bromoethoxy)benzo[d]thiazole

Title compound was prepared from benzo[d]thiazol-6-ol (1 g, 6.62 mmol)using the general methodology of Int-1 and afforded 0.39 g of6-(2-bromoethoxy)benzo[d]thiazole (Yield=23%).

6-(2-bromoethoxy)benzo[d]oxazole

Title compound was prepared from benzo[d]oxazol-6-ol (0.20 g, 1.48 mmol,1 equiv) using the general methodology of Intermediate-3. Purificationby column chromatography (20% EtOAc/Hexane) afforded 0.08 g of6-(2-bromoethoxy)benzo[d]oxazole (Yield=22%).

2-(2-chloroethoxy)-8-(trifluoromethyl)quinoline

To a stirred solution of 8-(trifluoromethyl)quinolin-2(1H)-one (100 mg,0.47 mmol) in DMF (1 mL) was added KOH (53 mg, 0.94 mmol) at 0° C. andthe mixture was stirred for 1 h. Then 1-bromo-2-chloroethane (135 mg,0.94 mmol) was added at 0° C. and the reaction mixture was stirred at RTfor 16 h. After completion, the reaction was quenched with aq.NH₄Cl andextracted with EtOAc. The organic layer was separated, dried over Na₂SO₄and concentrated under reduced pressure. The crude compound was purifiedby column chromatography eluting with 5% EtOAc in hexanes to obtain 90mg of 2-(2-chloroethoxy)-8-(trifluoromethyl)quinoline (Yield=70%).

3-(2-Bromoethoxy)-1,1′-biphenyl

Title compound was prepared from [1,1′-biphenyl]-3-ol (0.5 g, 2.94 mmol)using the general methodology of Intermediate-2. Purification usingsilica gel column chromatography (15% EtOAc/Hexanes) afforded 0.1 g of3-(2-bromoethoxy)-1,1′-biphenyl (Yield=12%).

(3-bromopropoxy)benzene

Title compound was prepared from phenol (5 g, 53.1 mmol) using thegeneral methodology of Intermediate-2 and afforded 9 g of(3-bromopropoxy)benzene (Yield=79%).

1-(3-Bromopropoxy)-2-(trifluoromethyl)benzene

Title compound was prepared from 2-(trifluoromethyl)phenol (1 g, 6.17mmol) using the general methodology of Intermediate-3. Purificationusing silica gel column chromatography (2% MeOH/DCM) afforded 1.2 g of4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine (Yield=69%).

(4-bromobutoxy)benzene

Title compound was prepared from phenol (5 g, 53.1 mmol) using thegeneral methodology of Intermediate-2 and afforded 10 g of(3-bromopropoxy)benzene (Yield=82%).

1-(4-Bromobutoxy)-2-fluorobenzene

Title compound was prepared from 2-fluorophenol (1 g, 8.9 mmol) usingthe general methodology of Intermediate-2 and afforded 0.64 g of1-(4-bromobutoxy)-2-fluorobenzene (Yield=29%).

1-(4-Bromobutoxy)-2-chlorobenzene

Title compound was prepared from 2-chlorophenol (1 g, 7.8 mmol) usingthe general methodology of Intermediate-2 and afforded 0.62 g of1-(4-bromobutoxy)-2-chlorobenzene (Yield=30%).

6-(4-Bromobutoxy)benzo[d]thiazole

Title compound was prepared from benzo[d]thiazol-6-ol (0.5 g, 3.31 mmol)using the general methodology of Intermediate-2. Purification usingsilica gel column chromatography (10% EtOAc/Hexanes) afforded 0.3 g of6-(4-bromobutoxy)benzo[d]thiazole (Yield=32%).

Ethyl 2-phenoxyacetate

Title compound was prepared from phenol (5 g, 53.1 mmol) and ethyl2-bromoacetate using the general methodology of Example-1. Purificationusing silica gel column chromatography (40% EtOAc/Hexanes as eluent) toafford 7.5 g of 1-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)-2-phenoxyethan-1-one (Yield=78%).

2-Phenoxyacetic acid

To a solution of ethyl 2-phenoxyacetate (2 g, 11.1 mmol) in 1:1:1mixture of THF/MeOH/H₂O (40 mL) was added lithium hydroxide monohydrateat 0° C. The reaction was stirred at room temperature for 12 h. Aftercompletion, the volatiles were removed under reduced pressure, dilutedwith water, neutralized with 1N HCl and the volatiles were removed underpressure. The residue was dissolved in EtOH (15 mL) and the solids werefiltered. The filtrate was concentrated under reduced pressure to afford1.6 g of 2-phenoxyacetic acid (Yield=95%).

ESI+MS: m/z 151 ([M−H]⁻).

2-Bromo-N-(2-(trifluoromethyl)phenyl)acetamide

To a solution of 2-(trifluoromethyl)aniline (0.5 g, 3.10 mmol) in CH₂Cl₂(5 mL) were added triethylamine (0.649 mL, 4.65 mmol, 1.5 equiv) and2-bromoacetyl bromide (0.75 g, 3.72 mmol, 1.2 equiv) at 0° C. Thereaction mixture was stirred at room temperature for 16 h. Aftercompletion, the reaction was diluted water and extracted with CH₂Cl₂.The organic extract was dried over sodium sulfate, filtered andconcentrated under reduced pressure. Purification using silica gelcolumn chromatography (15% EtOAc/Hexanes as eluent) to afford 0.2 g of2-bromo-N-(2-(trifluoromethyl)phenyl)acetamide (Yield=23%).

2-(2-(methylsulfonyl)phenoxy)ethyl methanesulfonate

2-(2-(methylsulfonyl)phenyl)ethan-1-ol

To a solution of 2-(methyl sulfonyl) phenol (1.0 g, 5.8 mmol) in acetone(20 mL) was added K₂CO₃ (1.61 g, 11.61 mmol) and 2-bromoethanol (2.18 g,17.4 mmol) at 0° C. The reaction mixture was heated at 60° C. andstirred for 6 h. After completion of the reaction (monitored by TLC),the reaction mass was diluted with water and extracted with EtOAc. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure to obtain crude material. The crude compound was purified bycolumn chromatography eluting with 3% MeOH in DCM to afford 0.9 g of2-(2-(methylsulfonyl)phenyl)ethan-1-ol as thick syrup (Yield=72%).

2-(2-(methylsulfonyl)phenoxy)ethyl methanesulfonate

To a stirred solution of 2-(2-(methylsulfonyl)phenyl)ethan-1-ol (0.1 g,0.46 mmol) in DCM (10 mL) cooled to 0° C. was added triethylamine (0.16mL, 1.16 mmol) followed by MsCl (0.04 mL, 0.51 mmol). The reactionmixture was stirred at RT for 16 h. After completion of the reaction(monitored by TLC), diluted with water and extracted with DCM. Theorganic layer was separated, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the crude. The crudecompound was purified by column chromatography eluent with 2% MeOH inDCM to afford 0.13 g of 2-(2-(methylsulfonyl)phenoxy)ethylmethanesulfonate as thick syrup (Yield=95%).

1-(4-(2-bromoethoxy)phenyl)ethanone

Title compound was prepared from 1-(4-hydroxyphenyl)ethanone (2.0 g,14.7 mmol) using the general methodology of Int-1 and afforded 2.0 g of1-(4-(2-bromoethoxy)phenyl)ethanone (Yield=56%).

1-(2-bromoethoxy)-4-(methylsulfonyl)benzene

Title compound was prepared from 4-(methylsulfonyl)phenol (0.2 g, 1.16mmol) using the general methodology of Int-3 and afforded 0.1 g of1-(2-bromoethoxy)-4-(methylsulfonyl)benzene (Yield=31%).

4-(2-bromoethoxy)benzonitrile

Title compound was prepared from 4-hydroxybenzonitrile (2.0 g, 16.79mmol) using the general methodology of Int-1 and afforded 0.4 g of4-(2-bromoethoxy)benzonitrile (Yield=11%).

1-(2-(2-bromoethoxy)-5-fluorophenyl)ethan-1-one

Title compound was prepared from 1-(5-fluoro-2-hydroxyphenyl)ethanone(0.5 g, 3.24 mmol) using the general methodology of Int-3 and afforded0.19 g of 1-(2-(2-bromoethoxy)-5-fluorophenyl)ethan-1-one (Yield=23%).

1-(2-bromoethoxy)-2-methoxybenzene

Title compound was prepared from 2-methoxyphenol (2.0 g, 16.11 mmol)using the general methodology of Int-2 and afforded 1.0 g of1-(2-bromoethoxy)-2-methoxybenzene (Yield=27%).

1-(2-bromoethoxy)-4,5-difluoro-2-methoxybenzene

Title compound was prepared from 4,5-difluoro-2-methoxyphenol (0.5 g,3.12 mmol) using the general methodology of Example-1 and afforded 0.3 gof 1-(2-bromoethoxy)-4,5-difluoro-2-methoxybenzene (Yield=36%).

1-(2-bromoethoxy)-4-fluoro-2-isopropoxybenzene

Title compound was prepared from 4-fluoro-2-isopropoxyphenol (0.25 g,1.47 mmol) using the general methodology of Example-1 and afforded 0.1 gof 1-(2-bromoethoxy)-4-fluoro-2-isopropoxybenzene (Yield=25%).

2-((3-(trifluoromethyl)pyridin-2-yl)oxy)ethyl methanesulfonate

((3-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-ol

To a stirred solution of 2-chloro-3-(trifluoromethyl)pyridine (300 mg,1.65 mmol) in DMF (2 mL) was added NaH (60% suspension, 132 mg, 3.3mmol) followed by ethylene glycol (411 mg, 6.6 mmol) at roomtemperature. The reaction mixture was heated at 100° C. for 16 h. Thereaction mass was diluted with water and extracted with ethyl acetate.The organic layer was dried over Na₂SO₄, filtered and concentratedPurification by column chromatography (eluting with 40% EtOAc in hexane)afforded 200 mg of 2-((3-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-ol(Yield=58%).

2-((3-(trifluoromethyl)pyridin-2-yl)oxy)ethyl methanesulfonate

To a stirred solution of 2-((3-(trifluoromethyl)pyridin-2-yl)oxy)ethanol(200 mg, 0.97 mmol) in DCM (10 mL) was added triethylamine (0.53 mL, 0.2mmol) followed by methanesulfonyl chloride (0.12 mL, 1.16 mmol) at 0° C.The reaction mixture was stirred at room temperature for 4 h. Aftercompletion, the reaction was diluted with water and extracted with DCM.The organic layer was dried over Na₂SO₄, filtered and concentrated toafford 200 mg of 2-((3-(trifluoromethyl)pyridin-2-yl)oxy)ethylmethanesulfonate (Yield=73%).

(S)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol

To a suspension of pyrocathecol (0.58 g, 5.26 mmol) and K₂CO₃ (0.73 g,5.26 mmol) in anhydrous DMF (22 mL), was added (2R)-(−)-glycidyltosylate (1.00 g, 4.38 mmol). The mixture was left stirring at 60° C.for 16 hours, then poured into ice-water and extracted with Et₂O untilthe organic phase was colorless. The organic layers were washed withbrine, dried over Na₂SO₄ filtered and concentrated. Purification byflash chromatography (hexanes/EtOAc 80:20) afforded the pure product aswhite solid (0.41 g, 56% yield). [α]_(D) ²⁵=−33.1° (EtOH; c=0.26).¹H-NMR (300 MHz, CDCl₃): δ 6.97-6.76 (m, 4H), 4.33-4.22 (m, 2H),4.17-4.05 (m, 1H), 3.87 (qd, J=11.9, 4.4 Hz, 2H). ESI-MS calcd forC₉H₁₀O₃ m/z 166.06, found 167.43 [M+H]⁺.

(R)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol

To a suspension of pyrocathecol (0.58 g, 5.26 mmol) and K₂CO₃ (0.73 g,5.26 mmol) in anhydrous DMF (22 mL) was added (2S)-(−)-glycidyl tosylate(1.00 g, 4.38 mmol). The mixture was left stirring at 60° C. for 16hours, then poured into ice-water and extracted with Et₂O until theorganic phase was colorless. The organic layers were washed with brine,dried over Na₂SO₄ and evaporated to give crude product. Purification byflash chromatography (n-hexane/EtOAc 80:20) afforded the pure product aswhite solid (0.43 g, 60% yield). [α]_(D) ²⁵=+32.5° (EtOH; c=0.20).¹H-NMR (400 MHz, CDCl₃): δ 6.95-6.79 (m, 4H), 4.33-4.22 (m, 2H),4.17-4.05 (m, 1H), 3.87 (qd, J=11.9, 4.4 Hz, 2H). ESI-MS calcd forC₉H₁₀O₃ m/z 166.06, found 167.43 [M+H]⁺.

(R)-2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine

A solution of (S)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol (0.40 g,2.41 mmol) and CBr₄ (0.87 g, 2.62 mmol) in CH₂Cl₂ (1.0 mL) was cooled to0° C. PPh₃ (0.69 g, 2.65 mmol) was added in portions over 30 min withvigorous stirring. Upon the addition of the phosphine, the colorlesssolution turned a pale brown color and was stirred for an additional 2 hat room temperature. The mixture was concentrated and n-hexane wasadded, the white precipitate filtered and purified by flashchromatography (n-hexane 100%) to obtain pure product as colorless oil(0.32 g, 58% yield). [α]_(D) ²⁵=−20.8° (EtOH; c=0.94). ¹H-NMR (400 MHz,CDCl₃): δ 6.92-6.83 (m, 4H), 4.44-4.38 (m, 1H), 4.35 (dd, J=11.5, 2.3Hz, 1H), 4.19 (dd, J=11.4, 5.9 Hz, 1H), 3.59-3.47 (m, 2H).

(S)-2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine

A solution of (R)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol (400 mg,2.41 mmol) and CBr₄ (870 mg, 2.62 mmol) in CH₂Cl₂ (1.0 mL) was cooled to0° C. PPh₃ (694 mg, 2.65 mmol) was added in portions over 30 min withvigorous stirring. Upon the addition of the phosphine, the colorlesssolution turned a pale brown color and was stirred for an additional 2 hat room temperature. The mixture was concentrated and hexane was added,the white precipitate filtered and purified by flash chromatography(n-hexane 100%) to obtain pure product as colorless oil (0.31 g, 56%yield). [α]_(D) ²⁵=+19.4° (EtOH; c=0.86). ¹H-NMR (400 MHz, CDCl₃): δ6.92-6.83 (m, 4H), 4.44-4.38 (m, 1H), 4.35 (dd, J=11.5, 2.3 Hz, 1H),4.19 (dd, J=11.4, 5.9 Hz, 1H), 3.59-3.47 (m, 2H).

(R)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl 4-methylbenzenesulfonate

To a solution of (S)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol (1.65g, 9.93 mmol) and Et₃N (2.78 mL, 19.86 mmol) in CH₂Cl₂ (10 mL) wasslowly added a solution of tosyl chloride (2.08 g, 10.92 mmol) in CH₂Cl₂(20 mL) at 0° C., under a N₂ atmosphere. The reaction mixture wasstirred at room temperature overnight, then poured into water (50 mL)and the aqueous layer was extracted with CH₂Cl₂. The organic layers werecombined and washed with 3M aq. sol. HCl, 2M aq. sol. Na₂CO₃, and H₂O.The organic phase was dried over MgSO₄ and concentrated. Purification byflash chromatography (n-hexane/EtOAc 80:20) afforded the pure product aswhite solid (2.42 g, 76% yield). [α]_(D) ²⁵=−13.6° (CHCl₃; c=0.60).¹H-NMR (300 MHz, Chloroform-d): δ 7.80 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.3Hz, 2H), 6.88-6.75 (m, 4H), 4.47-4.35 (m, 1H), 4.30-4.20 (m, 3H), 4.04(dd, J=11.6, 6.3 Hz, 1H), 2.46 (s, 3H). ESI-MS calcd for C₁₆H₁₆O₅S m/z320.07, found 320.20 [M]⁺.

(R)-2-(bromomethyl)-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine

To a solution of 5-fluoro-2-hydroxybenzaldehyde (0.31 g, 2.19 mmol) inan. DMF (0.9 mL) at room temperature was added (2R)-(−)-glycidyltosylate (0.50 g, 2.19 mmol) and K₂CO₃ (0.36 g, 2.63 mmol) and themixture was heated at 60° C. for 2 hours. The reaction was diluted withEt₂O and the organic phase washed with H₂O, 5% aq. LiCl and brine. Theorganic phase was dried over Na₂SO₄, filtered and removed under reducedpressure. Filtration over silica gave the epoxide intermediate, whichwas carried over in the next reaction.

The crude epoxide intermediate (0.33 g) was dissolved in an. CH₂Cl₂ (5.6mL), 3-chlorobenzoperoxoic acid (0.32 g, 1.85 mmol) was added and thesolution was left to stir for 90 minutes. The suspension was filteredand filtered over silica gel. The crude was dissolved in CH₃OH (3.5 mL)and Na₂CO₃ (100 mg) was added and the mixture was left stirringovernight. The mixture was diluted with water and neutralized with a 0.1M aq. HCl. The aqueous phase was extracted with CH₂Cl₂, the organicphases collected, dried over MgSO₄, filtered and concentrated.Filtration over silica gel gave a crude containing ˜50% of theintermediate alcohol and was carried over in the next reaction.

A solution of crude intermediate alcohol (190 mg) and CBr₄ (373 mg, 1.14mmol) in CH₂Cl₂ (0.45 mL) was cooled to 0° C. PPh₃ (298 mg, 0.13 mmol)was added under vigorous stirring.

Upon the addition of the phosphine, the colorless solution turned a palebrown color and was stirred overnight at room temperature. The mixturewas concentrated and n-hexane was added, the white precipitate filteredand purified by flash chromatography (n-hexane 100%) to afford 51 mg of(R)-2-(bromomethyl)-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine ascolorless oil (Yield=20%). [α]_(D) ²⁵=−5.0° (CHCl₃; c=0.65). ¹H-NMR (300MHz, Chloroform-d): δ 6.82 (dd, J=8.9, 5.4 Hz, 1H), 6.66-6.53 (m, 2H),4.47-4.36 (m, 1H), 4.32 (dd, J=11.6, 2.3 Hz, 1H), 4.16 (dd, J=11.5, 5.9Hz, 1H), 3.60-3.45 (m, 2H).

(R)-7-bromo-2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine

Title compound was prepared using the same strategy described above forthe synthesis of(R)-2-(bromomethyl)-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxine startingfrom 5-bromo-2-hydroxybenzaldehyde in place of5-fluoro-2-hydroxybenzaldehyde and afforded 60 mg of(R)-7-bromo-2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (Yield=56%).[α]_(D) ²⁵=−11.10 (CHCl₃; c=0.90). ¹H-NMR (400 MHz, Chloroform-d): δ7.06 (d, J=2.3 Hz, 1H), 6.96 (dd, J=8.6, 2.3 Hz, 1H), 6.77 (d, J=8.6 Hz,1H), 4.44-4.36 (m, 1H), 4.33 (dd, J=11.5, 2.3 Hz, 1H), 4.17 (dd, J=11.6,5.9 Hz, 1H), 3.58-3.46 (m, 2H).

Synthesis of Key Intermediate-I 3-(4-Chlorophenoxy)-3-methylpyrrolidine(Int-I)

tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate

To a stirred suspension of magnesium (2.59 g, 106 mmol, 1.97 equiv) in50 mL of dry ether were added iodine (catalytic) and methyl iodide (6.7mL, 108 mmol, 2 equiv) slowly drop wise at 0° C. under argon atmosphere.This was added to a solution of tert-butyl3-oxopyrrolidine-1-carboxylate (10 g, 54 mmol, 1 equiv) in 50 mL ofether at 0° C. The reaction mixture was warmed to room temperature andstirred for 1.5 h. After completion, the reaction was quenched withsaturated ammonium chloride solution at 0° C. and extracted with EtOAc.The combined organic extract was dried over sodium sulfate, filtered andconcentrated under reduced pressure. Purification using silica gelcolumn chromatography (20% EtOAc/hexanes) afforded 7.0 g of tert-butyl3-hydroxy-3-methylpyrrolidine-1-carboxylate (Yield=64%).

tert-butyl 3-methyl-3-(4-nitrophenoxy)pyrrolidine-1-carboxylate

To a suspension of sodium hydride (60% suspension, 0.99 g, 24.84 mmol, 2equiv) in 10 mL of dry THF was added tert-butyl3-hydroxy-3-methylpyrrolidine-1-carboxylate (2.5 g, 12.42 mmol, 1 equiv)in 15 mL of dry THF dropwise at 0° C. under argon atmosphere. Thereaction mixture was stirred for 15 min and 4-fluoro-nitrobenzene (2.63g, 18.66 mmol, 1.5 equiv) was added at 0° C. The reaction mixture washeated at 65° C. and stirred for 24 h. After completion, the reactionwas diluted with water and extracted with EtOAc. The combined organicextract was dried over sodium sulfate, filtered and concentrated underreduced pressure. Purification using column chromatography (20%EtOAc/hexanes) afforded 1 g of tert-butyl3-methyl-3-(4-nitrophenoxy)pyrrolidine-1-carboxylate (Yield 25%).

tert-butyl 3-(4-aminophenoxy)-3-methylpyrrolidine-1-carboxylate

To a solution of tert-butyl3-methyl-3-(4-nitrophenoxy)pyrrolidine-1-carboxylate (0.95 g, 2.95 mmol,1 equiv) in 10 mL of MeOH was added 10% Pd/C (0.25 g) under argonatmosphere. The reaction mixture was stirred at room temperature underhydrogen balloon pressure for 4 h. After completion, the reactionmixture was filtered through celite bed, washed with MeOH and thefiltrate was concentrated under reduced pressure to afford 0.8 g oftert-butyl 3-(4-aminophenoxy)-3-methylpyrrolidine-1-carboxylate (Yield93%).

3-(4-Chlorophenoxy)-3-methylpyrrolidine (Int-1)

To a solution of tert-butyl3-(4-aminophenoxy)-3-methylpyrrolidine-1-carboxylate (0.2 g, 0.68 mmol,1 equiv) in 3 mL of 50% aqueous HCl was added aqueous sodium nitrate(0.061 g, 0.889 mmol, 1.3 equiv) drop wise at 0° C. and stirred for 1 h.This was added to a solution of cuprous chloride (0.1 g, 1.09 mmol, 1.6equiv) in 1 mL of aqueous HCl at 0° C. and stirred at room temperaturefor 16 h. After completion, the pH was adjusted to 10 with aqueoussodium carbonate and extracted with EtOAc. The combined organic extractwas dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude was washed with n-hexane and dried under reducedpressure to afford 0.12 g of 3-(4-chlorophenoxy)-3-methylpyrrolidinealong with des chloro compound (Yield 83%). ESI+MS: m/z 212 [M+H]⁺.

Synthesis of Key Intermediate-II

tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate

Title compound was prepared from tert-butyl4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) using the generalmethodology of step 1 in key Intermediate-I. Purification using silicagel column chromatography (20% EtOAc/Hexane) afforded 2.4 g oftert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (Yield=44%).

tert-butyl 4-methyl-4-(4-nitrophenoxy)piperidine-1-carboxylate

To a suspension of sodium hydride (60% suspension, 0.36 g, 9.29 mmol, 2equiv) in 3 mL of dry THF was added tert-butyl4-hydroxy-4-methylpiperidine-1-carboxylate (1 g, 4.64 mmol, 1 equiv) indry THF (7 mL) drop wise at 0° C. The reaction mixture was stirred for15 min, 4-fluoro nitro benzene (0.98 g, 6.97 mmol, 1.5 equiv) was addedat 0° C. and the reaction was heated at 70° C. for 12 h. Aftercompletion, the reaction was quenched with ice cold water and extractedwith EtOAc. The organic extract was dried over sodium sulfate, filteredand concentrated under reduced pressure. Purification using silica gelcolumn chromatography (10% EtOAc/hexane as eluent) to afford 1.0 g oftert-butyl 4-methyl-4-(4-nitrophenoxy)piperidine-1-carboxylate(Yield=64%).

tert-butyl 4-(4-aminophenoxy)-4-methylpiperidine-1-carboxylate

Title compound was prepared from tert-butyl4-methyl-4-(4-nitrophenoxy)piperidine-1-carboxylate (1 g, 2.97 mmol)using the general methodology of step 3 in key Intermediate-I.Purification using silica gel column chromatography (40% EtOAc/Hexane)afforded 0.65 g tert-butyl4-(4-aminophenoxy)-4-methylpiperidine-1-carboxylate (Yield=71%). ESI+MS:m/z 307 ([M+H]⁺).

4-(4-Chlorophenoxy)-4-methylpiperidine (Int-II)

Title compound was prepared from tert-butyl4-(4-aminophenoxy)-4-methylpiperidine-1-carboxylate (0.25 g, 0.816 mmol)using the general methodology of step 4 in key Intermediate-I.Purification using silica gel column chromatography (40% EtOAc/Hexane)afforded 0.105 g 4-(4-chlorophenoxy)-4-methylpiperidine (Yield=57%).ESI+MS: m/z 226 ([M+H]⁺).

Key Intermediate-IV 3-Methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (Int-IV)

3-Methylpyrrolidin-3-ol hydrochloride

tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate (6 g, 29.8 mmol)was dissolved in methanol (80 mL) and the mixture was cooled to 0° C. Asolution of HCl in ether (2N, 66 mL) was then added and the reactionmixture was stirred at RT for 4 h. After completion of the reaction(monitored by TLC), solvent was completely removed and washed with etherto afford compound as brown solid. The crude was further washed withdiethyl ether to afford 2.8 g of 3-methylpyrrolidin-3-ol hydrochloride(Yield=68%).

3-Methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (Int-IV)

Title compound was prepared from 3-methylpyrrolidin-3-ol hydrochloride(0.9 g, 6.54 mmol) and (2-bromoethoxy)benzene (1.3 g, 6.54 mmol, 1equiv) using the general methodology of Example-1. Purification usingsilica gel column chromatography (5% MeOH/CH₂Cl₂) afforded 1.37 g of3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (Yield=95%).

Synthesis of Key Intermediate-V1-(2-(2-Fluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl) phenoxy)piperidine (Int-V)

tert-butyl 3-hydroxy-3-methylpiperidine-1-carboxylate

Title compound was prepared from N-Boc-3-piperidone (5 g, 25.09 mmol)using the general methodology of step 1 in Key Intermediate-I.Purification using silica gel column chromatography (30% EtOAc/Hexanesas eluent) to afford 1.1 g tert-butyl3-hydroxy-3-methylpiperidine-1-carboxylate (Yield=20%).

3-Methylpiperidin-3-ol hydrochloride (Int-V)

To a solution of tert-butyl 3-hydroxy-3-methylpiperidine-1-carboxylate(0.3 g, 1.39 mmol) in MeOH (5 mL) was added 4.0 M HCl in Dioxane (1.73mL) at 0° C. The reaction mixture was stirred at room temperature for 4h. After completion, volatiles were removed under reduced pressure toafford 0.15 g of 3-methylpiperidin-3-ol hydrochloride (Yield=71%).

Synthesis of Key Intermediate-VI

tert-butyl 4-methyl-4-phenoxypiperidine-1-carboxylate

tert-butyl 4-(4-aminophenoxy)-4-methylpiperidine-1-carboxylate (0.5 g,1.63 mmol) was dissolved in THF (10 mL) and cooled to 0° C. Isoamylnitrite (2.2 mL, 16.3 mmol) was then added and the reaction mixture wasstirred at 60° C. for 5 h. After completion of the reaction (monitoredby TLC), the mixture was diluted with water and extracted with diethylether and concentrated under reduced pressure to afford the crude. Thecrude compound was purified by column chromatography eluting with 5% EAin hexane to afford the product as thick syrup 0.30 g of tert-butyl4-methyl-4-phenoxypiperidine-1-carboxylate (Yield=63%).

4-Methyl-4-phenoxypiperidine hydrochloride (Int-VI)

To a solution of tert-butyl 4-methyl-4-phenoxypiperidine-1-carboxylate(0.25 g, 0.85 mmol) in diethyl ether (1 mL) was added 4 M HCl in1,4-Dioxane (1 mL) at room temperature. The reaction mixture was stirredat room temperature for 16 h. After completion, the reaction mass wasconcentrated under reduced pressure to afford 0.19 g of4-methyl-4-phenoxypiperidine hydrochloride (Quantitative).

Synthesis of Key Intermediate-VII

tert-butyl 3-methyl-3-phenoxypyrrolidine-1-carboxylate

To a stirred solution of tert-butyl3-(4-aminophenoxy)-3-methylpyrrolidine-1-carboxylate (0.2 g, 0.684 mmol)in THF (3 mL) was added isoamyl nitrite (0.27 mL, 2.05 mmol, 3 equiv) atroom temperature. The reaction mixture was heated at 75° C. for 3 h.After completion, the volatiles were removed under reduced pressure. Thecrude was diluted with EtOAc, washed with water, separated, dried oversodium sulfate and concentrated. Purification using silica gel columnchromatography (15% EtOAc/Hexane) afforded 0.11 g of tert-butyl3-methyl-3-phenoxypyrrolidine-1-carboxylate (Yield=58%). ESI+MS: m/z 278([M+H]⁺).

3-Methyl-3-phenoxypyrrolidine

To a stirred solution of tert-butyl3-methyl-3-phenoxypyrrolidine-1-carboxylate (0.1 g, 0.36 mmol) in CH₂Cl₂(3 mL) under argon atmosphere was added trifluoro acetic acid (1 mL) at0° C. The reaction mixture was warmed to room temperature and stirredfor 3 h. After completion of the reaction, volatiles were removed underreduced pressure, the pH was adjusted to ˜7 with saturated NaHCO₃solution and extracted with CH₂Cl₂. The combined organic extract wasdried over sodium sulfate, filtered and concentrated under reducedpressure to afford 0.05 g of 3-methyl-3-phenoxypyrrolidine (Yield=78%).ESI+MS: m/z 178 ([M+H]⁺).

Synthesis of Key Intermediate-IX 3-(4-Chlorophenoxy)-3-methylpiperidine(Int-IX)

tert-butyl 3-hydroxypiperidine-1-carboxylate

Title compound was prepared from tert-butyl3-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) using the generalmethodology of step 1 in Key Intermediate-I. Purification using silicagel column chromatography (15% EtOAc/hexanes) afforded 1.5 g oftert-butyl 3-hydroxypiperidine-1-carboxylate (Yield=27%).

tert-butyl 3-methyl-3-(4-nitrophenoxy)piperidine-1-carboxylate

Title compound was prepared from tert-butyl3-hydroxypiperidine-1-carboxylate (1 g, 4.64 mmol) and1-fluoro-4-nitrobenzene (0.98 g, 6.97 mmol, 1.5 equiv) using the generalmethodology of step 2 in Key Intermediate-I. Purification using silicagel column chromatography (15% EtOAc/hexanes) afforded 1 g of tert-butyl3-methyl-3-(4-nitrophenoxy)piperidine-1-carboxylate (Yield=64%).

tert-butyl 3-(4-aminophenoxy)-3-methylpiperidine-1-carboxylate

Title compound was prepared from tert-butyl3-methyl-3-(4-nitrophenoxy)piperidine-1-carboxylate (1 g, 2.97 mmol)using the general methodology of step 3 in Key Intermediate-I andafforded 0.78 g of tert-butyl3-(4-aminophenoxy)-3-methylpiperidine-1-carboxylate (Yield=86%). ESI+MS:m/z 307 ([M+H]⁺).

3-(4-Chlorophenoxy)-3-methylpiperidine(Int-IX)

Title compound was prepared from tert-butyl3-(4-aminophenoxy)piperidine-1-carboxylate (0.2 g, 0.65 mmol) usinggeneral methodology of step 4 in Key Intermediate-I and afforded 0.13 gof 3-(4-chlorophenoxy)-3-methylpiperidine (Yield=88%). ESI+MS: m/z 226([M+H]⁺).

Key Intermediate-X

4-Methylpiperidin-4-ol hydrochloride

To solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (5g, 23.2 mmol) in MeOH (5 mL) was added 4.0 M HCl in 1,4-Dioxane (17 mL)at 0° C. The reaction mixture was stirred at room temperature for 4 h.After completion, the volatiles were concentrated under reduced pressureto afford 3 g of 4-methylpiperidin-4-ol hydrochloride (Quantitative).

4-Methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol (Int-X)

Title compound was prepared from 4-methylpiperidin-4-ol hydrochloride (3g, 19.8 mmol) and 1-(2-bromoethoxy)-2-(trifluoromethyl)benzene usinggeneral methodology of step 2 in key intermediate-IV to afford 5 g of4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(Yield=83%).

Example-1: 3-(4-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

To a stirred solution of 3-(4-chlorophenoxy)-3-methylpyrrolidine (0.1 g,0.47 mmol) in 5 mL of CH₃CN were added potassium carbonate (0.19 g, 1.41mmol, 3 equiv) and (2-bromoethoxy)benzene (0.095 g, 0.47 mmol, 1 equiv)at room temperature. The reaction mixture was heated at 80° C. andstirred for 16 h. After completion, the reaction mixture was dilutedwith water and extracted with CH₂Cl₂. The combined organic extract wasdried over sodium sulfate, filtered and concentrated under reducedpressure. Purification using preparative HPLC afforded 0.035 g of3-(4-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl) pyrrolidine (Yield=22%).¹H NMR (400 MHz, DMSO-d₆): δ 7.30-7.25 (m, 4H), 6.97-6.90 (m, 5H), 4.05(t, J=6.0 Hz, 2H), 3.00 (d, J=10.0 Hz, 1H), 2.84-2.75 (m, 3H), 2.69-2.61(m, 2H), 2.21-2.14 (m, 1H), 1.95-1.89 (m, 1H), 1.45 (s, 3H); ESI+MS:m/z: 332 ([M+H]⁺).

Example-2: 3-(4-Chlorophenoxy)-1-(2-(2-methoxyphenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.11 g, 0.52 mmol) using the general methodology of Example-1. Thecrude material was purified by preparative HPLC purification to afford0.09 g of3-(4-chlorophenoxy)-1-(2-(2-methoxyphenoxy)ethyl)-3-methylpyrrolidine(Yield=47%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.26-7.23 (m, 2H), 6.97-6.94(m, 4H), 6.90-6.85 (m, 2H), 4.02 (t, J=6.0 Hz, 2H), 3.73 (s, 3H), 3.01(d, J=10.0 Hz, 1H), 2.83-2.75 (m, 3H), 2.69-2.62 (m, 2H), 2.18-2.14 (m,1H), 1.93-1.89 (m, 1H), 1.44 (s, 3H); ESI+MS: m/z: 362 ([M+H]⁺).

Example-3: 3-(4-chlorophenoxy)-3-methyl-1-(4-phenoxybutyl)pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.11 g, 0.52 mmol) using the general methodology of Example-1. Thecrude material was purified by preparative HPLC to afford 0.03 g of3-(4-chlorophenoxy)-3-methyl-1-(4-phenoxybutyl)pyrrolidine (Yield=15%).¹H NMR (400 MHz, DMSO-d₆): δ 7.29-7.24 (m, 4H), 6.96 (d, J=8.8 Hz, 2H),6.92-6.90 (m, 3H), 3.97 (t, J=6.4 Hz, 2H), 2.87 (br s, 1H), 2.67-2.62(m, 2H), 2.47-2.30 (m, 2H), 2.20-2.17 (m, 2H), 1.93-1.89 (m, 1H),1.77-1.70 (m, 2H), 1.62-1.57 (m, 2H), 1.42 (s, 3H); ESI+MS: m/z: 360([M+H]⁺).

Example-4: 3-(4-chlorophenoxy)-3-methyl-1-(3-phenoxypropyl)pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.10 g, 0.47 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (50% EtOAc/Hexane aseluent) to afford 0.068 g of3-(4-chlorophenoxy)-3-methyl-1-(3-phenoxypropyl)pyrrolidine (Yield=39%).¹H NMR (500 MHz, DMSO-d₆): δ 7.28-7.25 (m, 4H), 6.97-6.90 (m, 5H), 3.99(t, J=6.5 Hz, 2H), 2.89 (d, J=10.0 Hz, 1H), 2.70-2.50 (m, 6H), 2.21-2.16(m, 1H), 1.94-1.83 (m, 2H), 1.45 (s, 3H); ESI+MS: m/z: 346 ([M+H]⁺).

Example-5:3-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.10 g, 0.47 mmol) using the general methodology of Example-1. Thecrude was purified by preparative HPLC to afford 0.09 g of3-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-3-methylpyrrolidine(Yield=51%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.41 (dd, J=7.6, 1.2 Hz, 1H),7.31-7.24 (m, 3H), 7.15 (d, J=7.2 Hz, 1H), 6.97-6.92 (m, 3H), 4.15 (d,J=5.6 Hz, 2H), 3.07-3.04 (m, 1H), 2.84-2.80 (m, 3H), 2.75-2.71 (m, 2H),2.21-2.15 (m, 1H), 1.95-1.89 (m, 1H), 1.45 (s, 3H); ESI+MS: m/z: 366([M+H]⁺).

Example-6:3-(4-chlorophenoxy)-3-methyl-1-(2-(o-tolyloxy)ethyl)pyrrolidine

To a stirred solution of 3-(4-chlorophenoxy)-3-methylpyrrolidine (0.1 g,0.47 mmol) in 5 mL of CH₃CN were added potassium carbonate (0.196 g,1.41 mmol, 3 equiv) and (2-bromoethoxy)benzene (0.102 g, 0.47 mmol, 1equiv) at room temperature. The reaction mixture was heated at 65° C.and stirred for 12 h. After completion, the reaction mixture was dilutedwith water and extracted with EtOAc. The combined organic extract wasdried over sodium sulfate, filtered and concentrated under reducedpressure. Purification using silica gel column chromatography (4%MeOH/CH₂Cl₂ as eluent) to afford 0.036 g of3-(4-chlorophenoxy)-3-methyl-1-(2-(o-tolyloxy)ethyl)pyrrolidine(Yield=22%). ¹H NMR (400 MHz, CDCl₃): δ 7.26 (d, J=8.8 Hz, 2H), 7.13 (t,J=6.8 Hz, 2H), 6.97-6.91 (m, 3H), 6.82 (t, J=7.6 Hz, 1H), 4.07 (br s,2H), 3.02 (br s, 1H), 2.83 (s, 2H), 2.72-2.61 (m, 2H), 2.19-2.17 (m,2H), 2.14 (s, 3H), 1.94-1.93 (m, 1H), 1.46 (s, 3H); ESI+MS: m/z: 346([M+H]⁺).

Example-7:1-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethyl)pyridin-2(1H)-one

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) and 1-(2-chloroethyl)pyridin-2(1H)-one (0.082 g, 0.52mmol, 1.1 equiv) using the general methodology of Example-1. The crudewas purified by preparative HPLC to afford 0.12 g of1-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethyl)pyridin-2(1H)-one(Yield=76%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.62 (dd, J=7.0, 2.0 Hz, 1H),7.38 (dt, J=7.0, 2.0 Hz, 1H), 7.25 (d, J=8.5 Hz, 2H) 6.92 (d, J=9.5 Hz,2H), 6.35 (d, J=9.0 Hz, 1H), 6.17 (t, J=5.5 Hz, 1H), 3.95 (t, J=12.5 Hz,2H), 2.89 (d, J=9.5 Hz, 1H), 2.76-2.71 (m, 1H), 2.68-2.66 (m, 3H),2.61-2.57 (m, 1H), 2.17-2.12 (m, 1H), 1.89-1.84 (m, 1H), 1.41 (s, 3H);ESI+MS: m/z: 333 ([M+H]⁺).

Example-8:3-(4-chlorophenoxy)-3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.10 g, 0.47 mmol) and 1-(2-bromoethoxy)-2-(trifluoromethyl)benzene(0.12 g, 0.47 mmol, 1 equiv) using the general methodology of Example-1.The crude was purified by preparative HPLC to afford 0.05 g of3-(4-chlorophenoxy)-3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)pyrrolidine (Yield=25%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.60(d, J=7.6 Hz, 2H), 7.28-7.23 (m, 3H), 7.08 (t, J=7.6 Hz, 1H), 6.97-6.93(m, 2H), 4.20 (t, J=5.6 Hz, 2H), 3.00 (d, J=10.0 Hz, 1H), 2.87-2.77 (m,3H), 2.72-2.64 (m, 2H), 2.20-2.14 (m, 1H), 1.94-1.87 (m, 1H), 1.44 (s,3H), ESI+MS: m/z: 400 ([M+H]⁺).

Example-9:3-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified by preparative HPLC to afford 0.09 g of3-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-3-methylpyrrolidine(Yield=54%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.33-7.24 (m, 3H), 6.96 (d,J=8.8 Hz, 2H), 6.84-6.72 (m, 3H), 4.08 (t, J=6.0 Hz, 2H), 3.01 (d,J=10.0 Hz, 1H), 2.80-2.79 (m, 3H), 2.69-2.64 (m, 2H), 2.21-2.15 (m, 1H),1.95-1.89 (m, 1H), 1.45 (s, 3H), ESI+MS: m/z: 350 ([M+H]⁺).

Example-10:3-(4-chlorophenoxy)-1-(2-(3-chlorophenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) and 1-(2-bromoethoxy)-3-chlorobenzene (0.11 g, 0.47mmol, 1 equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC purification to afford 0.08 g of3-(4-chlorophenoxy)-1-(2-(3-chlorophenoxy)ethyl)-3-methylpyrrolidine(Yield=45%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.30-7.21 (m, 3H), 7.03-6.90(m, 5H), 4.09 (br s, 2H), 2.99 (br s, 1H), 2.79 (br s, 3H), 2.67-2.66(m, 2H), 2.20-2.17 (m, 1H), 1.94-1.90 (m, 1H), 1.45 (s, 3H); ESI+MS:m/z: 367 ([M+H]⁺).

Example-11:3-(4-chlorophenoxy)-3-methyl-1-(2-(m-tolyloxy)ethyl)pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.11 g, 0.52 mmol) using the general methodology of Example-1. Thecrude was purified by preparative HPLC purification to afford 0.1 g of3-(4-chlorophenoxy)-3-methyl-1-(2-(m-tolyloxy)ethyl)pyrrolidine(Yield=55%). ¹HNMR (400 MHz, DMSO-d₆): δ 7.26 (d, J=8.8 Hz, 2H), 7.14(t, J=8.8 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.75-6.70 (m, 3H), 4.03 (t,J=5.6 Hz, 2H), 3.00 (d, J=10.0 Hz, 1H), 2.82-2.76 (m, 3H), 2.69-2.63 (m,2H), 2.26 (s, 3H), 2.21-2.14 (m, 1H), 1.95-1.90 (m, 1H), 1.45 (s, 3H);ESI+MS: m/z: 346 ([M+H]⁺).

Example-12:3-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)pyridine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified by preparative HPLC purification to afford 0.035 g of3-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)pyridine(Yield=21%). ¹H NMR (500 MHz, DMSO-d₆): δ 8.28 (d, J=2.5 Hz, 1H), 8.15(d, J=4.5 Hz, 1H), 7.39-7.29 (m, 2H), 7.25 (d, J=8.5 Hz, 2H), 6.95 (d,J=8.5 Hz, 2H), 4.13 (t, J=6.0 Hz, 2H), 2.99 (d, J=10.5 Hz, 1H),2.85-2.76 (m, 3H), 2.68-2.62 (m, 2H), 2.20-2.14 (m, 1H), 1.94-1.88 (m,1H), 1.44 (s, 3H); ESI+MS: m/z: 333 ([M+H]⁺). The enantiomers of 12 wereseparated using chiral HPLC (method G) and afforded the pure enantiomers12a and 12b.

Example-13: 3-(4-chlorophenoxy)-3-methyl-1-(2-(3-(trifluoromethyl)phenoxy)ethyl) pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified by preparative HPLC to afford 0.09 g of3-(4-chlorophenoxy)-3-methyl-1-(2-(3-(trifluoromethyl)phenoxy)ethyl)pyrrolidine (Yield=47%). ¹H NMR (400 MHz, DMSO-d₆):δ 7.52 (t, J=8.0 Hz, 1H), 7.29-7.24 (m, 5H), 6.96 (d, J=8.8 Hz, 2H),4.17-4.14 (m, 2H), 3.02-3.00 (m, 1H), 2.81 (br s, 3H), 2.70-2.64 (m,2H), 2.22-2.15 (m, 1H), 1.95-1.89 (m, 1H), 1.45 (s, 3H); ESI+MS: m/z:400 ([M+H]⁺).

Example-14:3-(4-chlorophenoxy)-1-(2-(4-fluorophenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudematerial was purified by preparative HPLC to afford 0.067 g of3-(4-chlorophenoxy)-1-(2-(4-fluorophenoxy)ethyl)-3-methylpyrrolidine(Yield=40%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.23 (dd, J=6.8, 2.4 Hz, 2H),7.07 (t, J=8.8 Hz, 2H), 6.94-6.90 (m, 4H), 4.01 (t, J=5.6 Hz, 2H), 2.97(d, J=10.0 Hz, 1H), 2.78-2.76 (m, 3H), 2.66-2.61 (m, 2H), 2.18-2.12 (m,1H), 1.92-1.86 (m, 1H), 1.42 (s, 3H); ESI+MS: m/z: 350 ([M+H]⁺).

Example-15:3-(4-chlorophenoxy)-1-(2-(4-chlorophenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified by preparative HPLC to afford 0.086 g of3-(4-chlorophenoxy)-1-(2-(4-chlorophenoxy)ethyl)-3-methylpyrrolidine(Yield=49%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.32 (d, J=8.8 Hz, 2H), 7.27(d, J=8.8 Hz, 2H), 6.98-6.95 (m, 4H), 4.06 (s, 2H), 2.99 (br s, 1H),2.79 (br s, 3H), 2.67 (br s, 2H), 2.22-2.15 (m, 1H), 1.94-1.90 (m, 1H),1.45 (s, 3H); ESI+MS: m/z: 367 ([M+H]⁺).

Example-16:3-(4-Chlorophenoxy)-3-methyl-1-(2-(p-tolyloxy)ethyl)pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.09 g, 0.42 mmol) using the general methodology of Example-1. Thecrude material was purified by preparative HPLC to afford 0.07 g of3-(4-chlorophenoxy)-3-methyl-1-(2-(p-tolyloxy)ethyl)pyrrolidine(Yield=46%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.25 (d, J=8.5 Hz, 2H), 7.06(d, J=8.5 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.5 Hz, 2H), 4.00(t, J=6.0 Hz, 2H), 2.98 (d, J=10.0 Hz, 1H), 2.81-2.73 (m, 3H), 2.67-2.62(m, 2H), 2.21 (s, 3H), 2.16-2.15 (m, 1H), 1.92-1.89 (m, 1H), 1.44 (s,3H); ESI+MS: m/z: 346 ([M+H]⁺).

Example-17:3-(4-chlorophenoxy)-3-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (40% EtOAc/Hexanesas eluent) to afford 0.12 g of3-(4-chlorophenoxy)-3-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)pyrrolidine (Yield=60%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.64 (d, J=8.4 Hz,2H), 7.26 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.4 Hz,2H), 4.16 (s, 2H), 3.01 (br s, 1H), 2.82 (br s, 3H), 2.67 (br s, 2H),2.22-2.17 (m, 1H), 1.94-1.91 (m, 1H), 1.45 (s, 3H), ESI+MS: m/z: 400([M+H]⁺).

Example-18:6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)benzo[d]thiazole

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudematerial was purified by preparative HPLC to afford 0.07 g of6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)benzo[d]thiazole(Yield=38%). ¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 7.94 (d, J=9.0Hz, 1H), 7.73-7.72 (m, 1H), 7.24 (d, J=8.5 Hz, 2H), 7.13 (dd, J=9.0, 2.5Hz, 1H), 6.95 (d, J=8.5 Hz, 2H), 4.14 (t, J=6.0 Hz, 2H), 3.01 (d, J=10.0Hz, 1H), 2.87-2.79 (m, 3H), 2.70-2.62 (m, 2H), 2.19-2.16 (m, 1H),1.93-1.91 (m, 1H), 1.44 (s, 3H), ESI+MS: m/z: 389 ([M+H]⁺). Theenantiomers of 18 were separated using chiral HPLC (method I) andafforded the pure enantiomers 18a and 18b.

Example-19: 3-(4-chlorophenoxy)-1-(2-(3-methoxyphenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography to afford 0.11 g of3-(4-chlorophenoxy)-1-(2-(3-methoxyphenoxy)ethyl)-3-methyl pyrrolidine(Yield=64%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.25 (d, J=8.5 Hz, 2H), 7.15(t, J=7.5 Hz, 1H), 6.95 (d, J=8.5 Hz, 2H), 6.51-6.47 (m, 3H), 4.03 (t,J=5.0 Hz, 2H), 3.71 (s, 3H), 2.99 (d, J=10.5 Hz, 1H), 2.82-2.74 (m, 3H),2.67-2.62 (m, 2H), 2.18-2.16 (m, 1H), 1.92-1.89 (m, 1H), 1.44 (s, 3H);ESI+MS: m/z: 362 ([M+H]⁺).

Example-20: 3-(4-chlorophenoxy)-1-(2-(4-methoxyphenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography to afford 0.09 g of3-(4-chlorophenoxy)-1-(2-(4-methoxyphenoxy)ethyl)-3-methylpyrrolidine(Yield=52%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.25 (d, J=8.5 Hz, 2H), 6.95(d, J=8.5 Hz, 2H), 6.86-6.82 (m, 4H), 3.98 (t, J=5.5 Hz, 2H), 3.68 (s,3H), 2.98 (d, J=10.5 Hz, 1H), 2.77-2.71 (m, 3H), 2.67-2.62 (m, 2H),2.19-2.14 (m, 1H), 1.93-1.88 (m, 1H), 1.44 (s, 3H); ESI+MS: m/z: 362([M+H]⁺).

Example-21:3-(4-chlorophenoxy)-1-(2-(cyclohexyloxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.15 g, 0.70 mmol) and Intermediate-5 (0.147 g, 0.709 mmol, 1 equiv)using the general methodology of Example-1. Purification usingpreparative HPLC to afford 0.048 g of3-(4-chlorophenoxy)-1-(2-(cyclohexyloxy)ethyl)-3-methylpyrrolidine(Yield=20%). ¹HNMR (500 MHz, DMSO-d₆) δ: 7.27 (d, J=9.0 Hz, 2H), 6.95(d, J=9.0 Hz, 2H), 3.46 (t, J=6.0 Hz, 2H), 3.22-3.19 (m, 1H), 2.94 (d,J=10.0 Hz, 1H), 2.73-2.69 (m, 1H), 2.63-2.58 (m, 3H), 2.53-2.52 (m, 1H),2.17-2.12 (m, 1H), 1.90-1.85 (m, 1H), 1.81-1.76 (m, 2H), 1.64-1.60 (m,2H), 1.49-1.46 (m, 1H), 1.44 (s, 3H), 1.25-1.19 (m, 5H); ESI+MS: m/z:338 ([M+H]⁺).

Example-22:3-(4-chlorophenoxy)-1-(2-(2,4-difluorophenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1.Purification using preparative HPLC to afford 0.09 g of3-(4-chlorophenoxy)-1-(2-(2,4-difluorophenoxy)ethyl)-3-methylpyrrolidine(Yield=49%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.29-7.17 (m, 4H), 7.02-6.94(m, 3H), 4.12 (t, J=5.6 Hz, 2H), 3.00 (d, J=10.0 Hz, 1H), 2.85-2.76 (m,3H), 2.69-2.62 (m, 2H), 2.21-2.14 (m, 1H), 1.94-1.88 (m, 1H), 1.44 (s,3H); ESI+MS: m/z: 368 ([M+H]⁺).

Example-23:3-(4-chlorophenoxy)-1-(2-(2,5-difluorophenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1.Purification using preparative HPLC to afford 0.115 g of3-(4-chlorophenoxy)-1-(2-(2,5-difluorophenoxy)ethyl)-3-methylpyrrolidine(Yield=66%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.27-7.21 (m, 3H), 7.16-7.11(m, 1H), 6.96 (d, J=9.2 Hz, 2H), 6.77-6.72 (m, 1H), 4.15 (t, J=5.6 Hz,2H), 3.05-2.98 (m, 1H), 2.85-2.78 (m, 3H), 2.69-2.64 (m, 2H), 2.21-2.14(m, 1H), 1.95-1.88 (m, 1H), 1.44 (s, 3H); ESI+MS: m/z: 368 ([M+H]⁺).

Example-24:7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolone

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.09 g, 0.42 mmol) using the general methodology of Example-1.Purification using preparative HPLC to afford 0.04 g of7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy) quinolone(Yield=24%). ¹H NMR (500 MHz, DMSO-d₆): δ 8.81-8.80 (m, 1H), 8.27 (d,J=8.0 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.41-7.35 (m, 2H), 7.28-7.24 (m,3H), 6.97 (d, J=9.0 Hz, 2H), 4.25 (t, J=5.5 Hz, 2H), 3.04 (d, J=10.0 Hz,1H), 2.93-2.81 (m, 3H), 2.73-2.66 (m, 2H), 2.22-2.17 (m, 1H), 1.96-1.91(m, 1H), 1.46 (s, 3H); ESI+MS: m/z: 383 ([M+H]⁺).

Example-25:7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolin-2(1H)-one

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) and 7-(2-bromoethoxy)quinolin-2(1H)-one (0.12 g, 0.47mmol, 1.0 equiv) using the general methodology of Example-1. The crudewas purified by preparative HPLC to afford 0.035 g of7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolin-2(1H)-one(Yield=18%). ¹H NMR (500 MHz, DMSO-d₆): δ 11.57 (s, 1H), 7.79 (d, J=9.5Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.95 (d, J=8.5Hz, 2H), 6.79 (d, J=8.0 Hz, 2H), 6.28 (d, J=9.0 Hz, 1H), 4.09 (t, J=5.5Hz, 2H), 3.00 (d, J=10.0 Hz, 1H), 2.86-2.77 (m, 3H), 2.68-2.63 (m, 2H),2.18-2.16 (m, 1H), 1.93-1.90 (m, 1H), 1.44 (s, 3H); ESI+MS: m/z: 399([M+H]⁺).

Example-26: 3-(4-chlorophenoxy)-3-methyl-1-(3-phenylpropyl)pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.09 g, 0.42 mmol) and (3-bromopropyl)benzene (0.085 g, 0.425 mmol, 3equiv) using the general methodology of Example-1. Purification usingpreparative HPLC to afford 0.05 g of3-(4-chlorophenoxy)-3-methyl-1-(3-phenylpropyl)pyrrolidine (Yield=36%).¹H NMR (500 MHz, DMSO-d₆): δ 7.29-7.22 (m, 4H), 7.19-7.12 (m, 3H), 6.96(d, J=8.5 Hz, 2H), 2.89-2.86 (m, 1H), 2.73-2.55 (m, 5H), 2.42-2.38 (m,2H), 2.25-2.10 (m, 1H), 1.95-1.85 (m, 1H), 1.75-1.65 (m, 2H), 1.44 (s,3H); ESI+MS: m/z: 330 ([M+H]⁺).

Example-27:3-(4-chlorophenoxy)-1-(4-(2-fluorophenoxy)butyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified by preparative HPLC to afford 0.031 g of3-(4-chlorophenoxy)-1-(4-(2-fluorophenoxy)butyl)-3-methylpyrrolidine(Yield=17%). ¹H NMR (400 MHz, CD₃OD): δ 7.26-7.19 (m, 2H), 7.07-7.02 (m,3H), 6.93-6.86 (m, 3H), 4.06 (t, J=12.0 Hz, 2H), 3.10 (d, J=10.4 Hz,1H), 2.89-2.83 (m, 1H), 2.67-2.59 (m, 2H), 2.56-2.51 (m, 2H), 2.36-2.29(m, 1H), 2.00-1.93 (m, 1H), 1.85-1.79 (m, 2H), 1.76-1.68 (m, 2H), 1.49(s, 3H); ESI+MS: m/z: 378 ([M+H]⁺).

Example-28:3-(4-chlorophenoxy)-1-(4-(2-chlorophenoxy)butyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified using preparative HPLC to afford 0.03 g of3-(4-chlorophenoxy)-1-(4-(2-chlorophenoxy)butyl)-3-methylpyrrolidine(Yield=16%). ¹H NMR (400 MHz, CD₃OD): δ 7.35-7.32 (m, 1H), 7.25-7.20 (m,3H), 7.05-7.03 (m, 1H), 6.94-6.87 (m, 3H), 4.08 (t, J=12.0 Hz, 2H), 3.12(d, J=10.4 Hz, 1H), 2.91-2.85 (m, 1H), 2.70-2.57 (m, 4H), 2.38-2.31 (m,1H), 2.01-1.94 (m, 1H), 1.90-1.74 (m, 4H), 1.50 (s, 3H); ESI+MS: m/z:395 ([M+H]⁺).

Example-29:6-(4-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)butoxy)benzo[d]thiazole

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified using preparative HPLC to afford 0.03 g of6-(4-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)butoxy)benzo[d]thiazole(Yield=16%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.16 (s, 1H), 7.94 (d, J=8.8Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.12 (dd,J=8.8, 2.4 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 4.07 (t, J=6.4 Hz, 2H), 2.86(d, J=10.0 Hz, 1H), 2.66-2.54 (m, 2H), 2.45-2.42 (m, 3H), 2.20-2.14 (m,1H), 1.93-1.86 (m, 1H), 1.81-1.75 (m, 2H), 1.62-1.55 (m, 2H), 1.43 (s,3H), ESI+MS: m/z: 417 ([M+H]⁺).

Example-30:5-(2-(3-(4-Chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.05 g, 0.23 mmol) using the general methodology of Example-1. Thecrude was purified using preparative HPLC to afford 0.03 g of5-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine(Yield=32%). ¹H NMR (400 MHz, CD₃OD): δ 8.38 (d, J=2.8 Hz, 1H), 7.75 (d,J=8.8 Hz, 1H), 7.56 (dd, J=8.8, 2.4 Hz, 1H), 7.23-7.19 (m, 2H),6.95-6.91 (m, 2H), 4.28 (t, J=5.6 Hz, 2H), 3.22 (d, J=10.4 Hz, 1H),3.05-2.92 (m, 3H), 2.80-2.74 (m, 2H), 2.39-2.33 (m, 1H), 2.03-1.97 (m,1H), 1.52 (s, 3H); ESI+MS: m/z: 401 ([M+H]⁺).

Example-31: 3-(4-Chlorophenoxy)-3-methyl-1-(2-(naphthalen-2-yloxy)ethyl)pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified by preparative HPLC to afford 0.07 g of3-(4-chlorophenoxy)-3-methyl-1-(2-(naphthalen-2-yloxy)ethyl)pyrrolidine(Yield=39%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.80 (t, J=9.6 Hz, 3H), 7.45(t, J=7.2 Hz, 1H), 7.35-7.31 (m, 2H), 7.26 (d, J=9.2 Hz, 2H), 7.14 (dd,J=9.2, 2.8 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 4.19 (t, J=5.6 Hz, 2H), 3.04(d, J=10.4 Hz, 1H), 2.94-2.80 (m, 3H), 2.73-2.65 (m, 2H), 2.23-2.16 (m,1H), 1.97-1.90 (m, 1H), 1.46 (s, 3H); ESI+MS: m/z: 382 ([M+H]⁺).

Example-32:6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolone

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified using preparative HPLC to afford 0.04 g of6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolone(Yield=22%). ¹HNMR (500 MHz, DMSO-d₆): δ 8.73-8.72 (m, 1H), 8.23 (d,J=8.5 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.48-7.45 (m, 1H), 7.42-7.39 (m,2H), 7.25 (d, J=9.0 Hz, 2H), 6.97 (d, J=8.5 Hz, 2H), 4.21 (t, J=11.0 Hz,2H), 3.04 (d, J=10.5 Hz, 1H), 2.93-2.81 (m, 3H), 2.73-2.63 (m, 2H),2.21-2.18 (m, 1H), 1.95-1.92 (m, 1H), 1.46 (s, 3H), ESI+MS: m/z: 383([M+H]⁺).

Example-33:6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)isoquinoline

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified using preparative HPLC to afford 0.02 g of6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)isoquinoline(Yield=11%). ¹H NMR (500 MHz, DMSO-d₆): δ 9.14 (s, 1H), 8.39 (d, J=6.0Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.68 (d, J=6.0 Hz, 1H), 7.36 (s, 1H),7.31-7.29 (m, 1H), 7.25 (d, J=7.2 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 4.24(t, J=12.0 Hz, 2H), 3.04 (d, J=10.0 Hz, 1H), 2.94-2.81 (m, 3H),2.73-2.66 (m, 2H), 2.22-2.17 (m, 1H), 1.96-1.91 (m, 1H), 1.46 (s, 3H);ESI+MS: m/z: 383 ([M+H]⁺).

Example-34:7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)isoquinoline

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.05 g, 0.23 mmol) using the general methodology of Example-1. Thecrude was purified using preparative HPLC to afford 0.02 g of7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)isoquinoline(Yield=22%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.36 (d, J=5.2Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.74 (d, J=5.6 Hz, 1H), 7.54-7.53 (m,1H), 7.43 (dd, J=9.6, 2.4 Hz, 1H), 7.27-7.23 (m, 2H), 6.98-6.95 (m, 2H),4.23 (t, J=5.6 Hz, 2H), 3.04 (d, J=10.0 Hz, 1H), 2.95-2.81 (m, 3H),2.73-2.66 (m, 2H), 2.23-2.16 (m, 1H), 1.97-1.90 (m, 1H), 1.46 (s, 3H);ESI+MS: m/z: 383 ([M+H]⁺).

Example-35:3-(4-chlorophenoxy)-1-(2-(3,4-dichlorophenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified using preparative HPLC to afford 0.05 g of3-(4-chlorophenoxy)-1-(2-(3,4-dichlorophenoxy)ethyl)-3-methylpyrrolidine(Yield=26%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.50 (d, J=9.2 Hz, 1H),7.28-7.24 (m, 3H), 6.98-6.93 (m, 3H), 4.09 (t, J=5.6 Hz, 2H), 2.99 (d,J=10.0 Hz, 1H), 2.85-2.72 (m, 3H), 2.68-2.60 (m, 2H), 2.21-2.14 (m, 1H),1.95-1.88 (m, 1H), 1.44 (s, 3H); ESI+MS: m/z: 401 ([M+H]⁺).

Example-36: 3-(4-chlorophenoxy)-3-methyl-1-(2-(naphthalen-1-yloxy)ethyl)pyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified using preparative HPLC to afford 0.07 g of3-(4-chlorophenoxy)-3-methyl-1-(2-(naphthalen-1-yloxy)ethyl)pyrrolidine(Yield=39%). ¹H NMR (400 MHz, CD₃OD): δ 8.25 (d, J=8.0 Hz, 1H), 7.81 (d,J=7.2 Hz, 1H), 7.51-7.43 (m, 3H), 7.39 (t, J=7.6 Hz, 1H), 7.16 (d,J=8.00 Hz, 2H), 6.92 (d, J=8.8 Hz, 3H), 4.35 (t, J=5.2 Hz, 2H),3.36-3.31 (m, 1H), 3.18-3.05 (m, 3H), 2.88-2.84 (m, 2H), 2.42-2.35 (m,1H), 2.07-2.00 (m, 1H), 1.54 (s, 3H); ESI+MS: m/z: 382 ([M+H]⁺).

Example-37:1-(2-([1,1′-biphenyl]-3-yloxy)ethyl)-3-(4-chlorophenoxy)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.1 g, 0.47 mmol) using the general methodology of Example-1. The crudewas purified using preparative HPLC to afford 0.029 g of1-(2-([1,1′-biphenyl]-3-yloxy)ethyl)-3-(4-chlorophenoxy)-3-methylpyrrolidine(Yield=15%). ¹H NMR (400 MHz, CD₃OD): δ 7.60-7.58 (m, 2H), 7.42 (t,J=7.6 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.19-7.15 (m, 4H), 6.92 (d, J=6.8Hz, 3H), 4.19 (t, J=5.6 Hz, 2H), 3.24 (d, J=10.8 Hz, 1H), 3.01-2.88 (m,3H), 2.79-2.72 (m, 2H), 2.38-2.31 (m, 1H), 2.02-1.95 (m, 1H), 1.51 (s,3H); ESI+MS: m/z: 408 ([M+H]⁺).

Example-38: 4-(4-chlorophenoxy)-4-methyl-1-(2-phenoxyethyl)piperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.1 g, 0.443 mmol) using the general methodology of Example-1. Thecrude was purified by preparative HPLC to afford 0.066 g of4-(4-chlorophenoxy)-4-methyl-1-(2-phenoxyethyl)piperidine (Yield=43%).¹H NMR (500 MHz, DMSO-d₆): δ 7.31-7.24 (m, 4H), 7.00 (d, J=8.5 Hz, 2H),6.90 (d, J=8.0 Hz, 3H), 4.05 (t, J=6.0 Hz, 2H), 2.71-2.69 (m, 2H),2.52-2.48 (m, 4H), 1.86-1.83 (m, 2H), 1.64-1.59 (m, 2H), 1.22 (s, 3H);ESI+MS: m/z: 346 ([M+H]⁺).

Example-39: 3-methyl-3-phenoxy-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from 3-methyl-3-phenoxypyrrolidine (0.05 g,0.282 mmol) and (2-bromoethoxy)benzene (0.057 g, 0.282 mmol, 1 equiv)using the general methodology of Example-1. The crude was purified bypreparative HPLC purification to afford 0.06 g of3-(4-chlorophenoxy)-1-(2-(2-methoxyphenoxy)ethyl)-3-methylpyrrolidine(Yield=70%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.28-7.21 (m, 4H), 6.92-6.89(m, 6H), 4.05 (t, J=5.5 Hz, 2H), 3.00 (d, J=10.0 Hz, 1H), 2.83-2.78 (m,3H), 2.71-2.65 (m, 2H), 2.22-2.17 (m, 1H), 1.94-1.88 (m, 1H), 1.45 (s,3H), ESI+MS: m/z: 298 ([M+H]⁺).

Example-40: 3-Methyl-3-(3-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.15 g, 0.67 mmol) and1-fluoro-3-nitro benzene (0.096 g, 0.67 mmol, 1 equiv) using the generalmethodology of step 2 of key Intermediate-I. Purification using silicagel column chromatography (2% MeOH/CH₂Cl₂) to afford 0.11 g of3-methyl-3-(3-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine (Yield=47%).¹H NMR (500 MHz, DMSO-d₆): δ 7.81-7.78 (m, 2H), 7.71-7.68 (m, 1H), 7.53(t, J=8.5 Hz, 2H), 7.44-7.42 (m, 1H), 7.27 (t, J=7.5 Hz, 2H), 6.92 (d,J=7.5 Hz, 1H), 4.41-4.12 (m, 1H), 4.07 (t, J=5.5 Hz, 1H), 3.11 (d,J=10.5 Hz, 1H), 2.92-2.78 (m, 2H), 2.74-2.64 (m, 1H), 2.27-2.22 (m, 1H),2.01-1.96 (m, 1H), 1.53 (s, 3H), 1.28-1.23 (m, 2H); ESI+MS: m/z: 343([M+H]⁺).

Example-41: 3-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

Title compound was prepared from3-methyl-3-(3-nitrophenoxy)-1-(2-phenoxyethyl) pyrrolidine (0.20 g, 0.58mmol) using the general methodology of step 3 of Key Intermediate-I.Purification using silica gel column chromatography (2% MeOH/CH₂Cl₂) toafford 0.11 g of3-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline (Yield=60%).¹H NMR (400 MHz, DMSO-d₆): δ 7.29-7.25 (m, 2H), 6.94-6.91 (m, 3H),6.86-6.82 (m, 1H), 6.16-6.14 (m, 2H), 6.07-6.04 (m, 1H), 4.95 (br s,2H), 4.06-4.03 (m, 2H), 2.94 (d, J=10.0 Hz, 1H), 2.83-2.74 (m, 2H),2.73-2.65 (m, 3H), 2.20-2.13 (m, 1H), 1.89-1.83 (m, 1H), 1.43 (s, 3H);ESI+MS: m/z: 313 ([M+H]⁺).

Example-42: 3-(3-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy) aniline (0.11 g,0.35 mmol) using the general methodology of step 4 of KeyIntermediate-I. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂) to afford 0.032 g of3-(3-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (Yield=26%).¹H NMR (400 MHz, CD₃OD): δ 7.28-7.18 (m, 3H), 6.97-6.88 (m, 6H), 4.13(t, J=5.6 Hz, 2H), 3.31-3.25 (m, 1H), 3.00-2.89 (m, 3H), 2.80-2.77 (m,2H), 2.40-2.34 (m, 1H), 2.06-1.99 (m, 1H), 1.54 (s, 3H), ESI+MS: m/z:332 ([M+H]⁺).

Example-43: 3-Methyl-3-(4-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine

To a stirred solution of 3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.3g, 1.35 mmol, 1 equiv) in 8 mL of THF was added sodium hydride (60%suspension, 0.08 g, 2.03 mmol, 1.5 equiv) at 0° C. under argonatmosphere followed by 1-fluoro-4-nitrobenzene (0.19 g, 1.35 mmol, 1equiv). The reaction was heated at 80° C. for 24 h, after completion,the reaction was quenched with ice cold water and extracted with ether.The organic extract was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The combined organic extract wasdried over sodium sulfate, filtered and concentrated under reducedpressure. Purification using column chromatography (2% MeOH/CH₂Cl₂) toafford 0.28 g of3-methyl-3-(4-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine (Yield=60%).¹H NMR (500 MHz, DMSO-d₆): δ 8.14 (d, J=9.0 Hz, 2H), 7.29-7.25 (m, 2H),7.15 (d, J=9.0 Hz, 2H), 6.94-6.90 (m, 3H), 4.08-4.05 (m, 2H), 3.09 (d,J=10.0 Hz, 1H), 2.83-2.78 (m, 4H), 2.67-2.63 (m, 1H), 2.27-2.21 (m, 1H),2.09-2.03 (m, 1H), 1.57 (s, 3H), ESI+MS: m/z: 343 ([M+H]⁺).

Example-44: 4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

Title compound was prepared from3-methyl-3-(4-nitrophenoxy)-1-(2-phenoxyethyl) pyrrolidine (0.24 g, 0.7mmol) using the general methodology of step 3 of Key Intermediate-I. Thecrude was purified using silica gel column chromatography (2%MeOH/CH₂Cl₂) to afford 0.18 g of4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline (Yield=80%).¹HNMR (500 MHz, DMSO-d₆): δ 7.30-7.27 (m, 2H), 6.95-6.92 (m, 3H), 6.66(d, J=9.0 Hz, 2H), 6.45 (d, J=9.0 Hz, 2H), 5.01 (br s, 2H), 4.08 (br s,2H), 2.86-2.64 (m, 6H), 2.15-2.12 (m, 1H), 1.77 (br s, 1H), 1.32 (s,3H); ESI+MS: m/z: 313 ([M+H]⁺).

Example-45: 3-methyl-3-(2-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.30 g, 1.35 mmol) and2-fluoro nitro benzene (0.19 g, 1.35 mmol, 1 equiv) using the generalmethodology of step 2 of Key intermediate-I. Purification using silicagel column chromatography (2% MeOH/CH₂Cl₂) to afford 0.27 g of3-methyl-3-(2-nitrophenoxy)-1-(2-phenoxyethyl) pyrrolidine (Yield=56%).¹H NMR (500 MHz, DMSO-d₆): δ 7.79-7.78 (m, 1H), 7.56-7.52 (m, 1H), 7.41(d, J=8.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.13-7.10 (m, 1H), 6.94-6.90 (m,3H), 4.05 (t, J=5.5 Hz, 2H), 3.02-3.00 (m, 1H), 2.81-2.75 (m, 4H),2.70-2.63 (m, 1H), 2.24-2.19 (m, 1H), 2.03-1.97 (m, 1H), 1.52 (s, 3H);ESI+MS: m/z: 343 ([M+H]⁺).

Example-46: 2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

Title compound was prepared from3-methyl-3-(2-nitrophenoxy)-1-(2-phenoxyethyl) pyrrolidine (0.25 g, 0.73mmol) using the general methodology of step 3 of Key Intermediate-I.Purification using silica gel column chromatography (2% MeOH/CH₂Cl₂) toafford 0.11 g of2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline (Yield=48%).¹H NMR (500 MHz, DMSO-d₆): δ 7.29 (t, J=8.0 Hz, 2H), 6.95-6.92 (m, 3H),6.66 (d, J=9.0 Hz, 2H), 6.45 (d, J=9.0 Hz, 2H), 4.95 (br s, 2H), 4.08(br s, 2H), 2.86 (br s, 6H), 2.15-2.12 (m, 1H), 1.77 (br s, 1H), 1.32(s, 3H); ESI+MS: m/z: 313 ([M+H]⁺).

Example-47: 3-(2-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline (0.09 g,0.288 mmol) using the general methodology of step 4 of KeyIntermediate-I to afford 0.02 g of3-(2-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (Yield=21%).¹HNMR (400 MHz, CDCl₃): δ 7.35 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.30-7.27 (m,2H), 7.14-7.10 (m, 1H), 7.07-7.04 (m, 1H), 6.96-6.88 (m, 4H), 4.10 (t,J=6.0 Hz, 2H), 3.16 (d, J=10.0 Hz, 1H), 2.95-2.80 (m, 5H), 2.47-2.40 (m,1H), 2.01-1.94 (m, 1H), 1.55 (s, 3H); ESI+MS: m/z: 332 ([M+H]⁺).

Example-48:3-(2,4-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

3-(2-chloro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.80 g, 3.62 mmol) and2-chloro-1-fluoro-4-nitrobenzene (0.69 g, 3.98 mmol, 1.1 equiv) usingthe general methodology of step 2 of key intermediate-I. The crude waspurified using silica gel column chromatography (2% MeOH/CH₂Cl₂) toafford 0.6 g of3-(2-chloro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(Yield=44%). ESI+MS: m/z 377 ([M+H]⁺).

3-chloro-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

To a stirred solution of3-(2-chloro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (0.5g, 1.32 mmol) in acetic acid (3 mL) under argon atmosphere was addedZn-dust (0.26 g, 3.98 mmol, 3 equiv) at 0° C. The reaction was stirredat room temperature for 16 h. After completion, the volatiles wereremoved under reduced pressure, the pH was adjusted to ˜8 with 10%NaHCO₃ solution and extracted with EtOAc. The combined organic extractwas dried over sodium sulfate, filtered and concentrated under reducedpressure to afford 0.3 g of3-(2-chloro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(Yield=65%). Ion trap: m/z 347 ([M+H]⁺).

3-(2,4-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

To a solution of3-chloro-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline in a2 mL of a 1:1 mixture of aqueous HCl was added aqueous sodium nitrite(0.064 g, 0.93 mmol, 1.3 equiv) drop wise at 0° C. and stirred for 1 h.This was added to a solution of cuprous chloride (0.11 g, 1.15 mmol, 1.6equiv) in 1 mL of aqueous HCl at 0° C. and stirred at room temperaturefor 1 h. After completion, the pH was adjusted to 14 with aqueous sodiumhydroxide and extracted with EtOAc. The combined organic extract wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The crude was washed with n-hexane and dried under reducedpressure to afford 0.015 g of3-(2,4-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (Yield17%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.55 (br s, 1H), 7.29-7.25 (m, 4H),6.94-6.92 (m, 3H), 4.05 (t, J=6.0 Hz, 2H), 3.05 (d, J=10.0 Hz, 1H),2.81-2.75 (m, 4H), 2.67-2.66 (m, 1H), 2.25-2.19 (m, 1H), 1.98-1.93 (m,1H), 1.48 (s, 3H); ESI+MS: m/z: 367 ([M+H]⁺).

Example-49:3-(2,4-Dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

3-(3-Chloro-2-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.25 g, 1.13 mmol) and1-chloro-3-fluoro-2-nitrobenzene (0.218 g, 1.24 mmol, 1.1 equiv) usingthe general methodology of step 2 of key intermediate-I. Purificationusing silica gel column chromatography (2% MeOH/CH₂Cl₂) to afford 0.2 gof 3-(3-chloro-2-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(Yield=47%). ESI+MS: m/z 377 ([M+H]⁺).

2-Chloro-6-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

To a stirred solution of3-(3-chloro-2-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (0.2g, 0.531 mmol) in acetic acid (2 mL) under argon atmosphere was addedZn-dust (0.104 g, 1.59 mmol, 3 equiv) at 0° C. The reaction mixture washeated at 80° C. and stirred for 4 h. After completion, the volatileswere removed under reduced pressure, the pH was adjusted to ˜8 with 10%NaHCO₃ solution and extracted with EtOAc. The combined organic extractwas dried over sodium sulfate, filtered and concentrated under reducedpressure to afford 0.13 g of2-chloro-6-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(Yield=70%).

3-(2,3-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from2-chloro-6-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(0.13 g, 0.375 mmol, 1 equiv) using general methodology of step 4 of keyintermediate-I. The crude was purified by preparative HPLC purificationto afford 0.015 g of3-(2,3-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(Yield=10%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.29-7.22 (m, 5H), 6.94-6.90(m, 3H), 4.06 (br s, 2H), 3.07-3.05 (m, 1H), 2.82-2.80 (m, 4H),2.69-2.63 (m, 1H), 2.25 (br s, 1H), 2.01-2.00 (m, 1H), 1.51 (s, 3H);ESI+MS: m/z: 367 ([M+H]⁺).

Example-50:3-(2,3-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

3-(3-Chloro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.25 g, 1.13 mmol) and2-chloro-4-fluoro-1-nitrobenzene (0.218 g, 1.24 mmol, 1.1 equiv) usingthe general methodology of step 2 of key intermediate-I. The crude waspurified using silica gel column chromatography (40% EtOAc/Hexane) toafford 0.2 g of3-(3-chloro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(Yield=47%). ESI+MS: m/z 377 ([M+H]⁺).

2-chloro-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

Title compound was prepared from3-(3-chloro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (0.20g, 0.53 mmol) using the general methodology of step 2 of Example-49 toafford 0.149 g of2-chloro-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(Yield=81%).

3-(2,3-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from2-chloro-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(0.15 g, 0.43 mmol, 1 equiv) using general methodology of step 4 of keyintermediate-I. The crude was purified by preparative HPLC purificationto afford 0.015 g of3-(2,3-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(Yield=9%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.45 (d, J=9.0 Hz, 1H),7.29-7.21 (m, 3H), 6.99-6.95 (m, 1H), 6.93-6.88 (m, 3H), 4.05 (t, J=5.5Hz, 2H), 3.04 (d, J=10.0 Hz, 1H), 2.85-2.77 (m, 3H), 2.70-2.61 (m, 2H),2.21-2.16 (m, 1H), 1.97-1.91 (m, 1H), 1.47 (s, 3H); ESI+MS: m/z: 367([M+H]⁺).

Example-51: 3-(4-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

3-(4-fluoro-2-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.8 g, 3.62 mmol) and1,4-difluoro-2-nitrobenzene (0.633 g, 3.98 mmol, 1.1 equiv) using thegeneral methodology of step 2 of key intermediate-I. The crude waspurified using silica gel column chromatography (30% EtOAc/Hexane) toafford 0.6 g of3-(4-fluoro-2-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(Yield=46%). ESI+MS: m/z 361 ([M+H]⁺).

5-fluoro-2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

Title compound was prepared from3-(4-fluoro-2-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (0.6g, 1.66 mmol) using the general methodology of step 3 of keyintermediate-I. The crude was purified using silica gel columnchromatography (30% EtOAc/Hexane) to afford 0.39 g of5-fluoro-2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(Yield=71%). ESI+MS: m/z 331 ([M+H]⁺).

3-(4-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

To a stirred solution of5-fluoro-2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(0.25 g, 0.757 mmol, 1 equiv) in 5 mL of THF was added tert-butylnitrite (0.78 g, 7.57 mmol, 1 equiv). The reaction was stirred at roomtemperature for 16 h; after completion, the reaction was quenched withice cold water and extracted with ethyl acetate. The organic extract wasdried over sodium sulfate, filtered and concentrated under reducedpressure. Purification by preparative HPLC to afford 0.025 g of3-(4-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (Yield=10%).¹H NMR (400 MHz, CD₃OD): δ 7.29-7.24 (m, 2H), 6.97-6.91 (m, 7H), 4.13(t, J=5.6 Hz, 2H), 3.23 (d, J=10.8 Hz, 1H), 3.04-2.96 (m, 2H), 2.92-2.87(m, 1H), 2.80-2.74 (m, 1H), 2.69 (d, J=10.8 Hz, 1H), 2.37-2.30 (m, 1H),1.98-1.91 (m, 1H), 1.47 (s, 3H); ESI+MS: m/z: 316 ([M+H]⁺).

Example-52: 3-(3-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

To a stirred solution of4-fluoro-2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(0.15 g, 0.454 mmol) in THF (1 mL) under argon atmosphere was addedBF₃.Et₂O (0.064 g, 0.454 mmol, 1 equiv) and tert-butyl nitrite (0.06 g,0.545 mmol, 1.2 equiv). The reaction was stirred at room temperature for16 h. After completion, the volatiles removed under reduced pressure;the pH was adjusted to 7 using saturated NaHCO₃ and extracted withCH₂Cl₂. The organic extract was dried over sodium sulfate, filtered andconcentrated. Purification by preparative HPLC afforded 0.01 g of3-(3-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (Yield=6%).¹H NMR (400 MHz, DMSO-d₆): δ 7.28-7.19 (m, 3H), 6.94-6.90 (m, 3H),6.78-6.67 (m, 3H), 4.14 (t, J=5.6 Hz, 2H), 3.31-3.30 (m, 1H), 3.00-2.92(m, 3H), 2.83-2.77 (m, 2H), 2.42-2.35 (m, 1H), 2.07-2.00 (m, 1H), 1.55(s, 3H); ESI+MS: m/z: 316 ([M+H]⁺).

Example-53: 3-(3-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

3-(2-Fluoro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (1 g, 4.52 mmol) and1,2-difluoro-4-nitrobenzene (0.79 g, 4.97 mmol, 1.1 equiv) using thegeneral methodology of step 2 of key intermediate-I. Purification usingsilica gel column chromatography (2% MeOH/CH₂Cl₂) to afford 0.8 g of3-(2-fluoro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(Yield=49%). ESI+MS: m/z 361 ([M+H]⁺).

3-Fluoro-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

Title compound was prepared from3-(2-fluoro-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (0.7g, 1.94 mmol) using the general methodology of step 3 of keyintermediate-I to afford 0.5 g of3-fluoro-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(Yield=78%). ESI+MS: m/z 331 ([M+H]⁺).

3-(3-Fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-fluoro-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(0.25 g, 0.757 mmol) using the general methodology of Example 51.Purification using silica gel column chromatography (5% MeOH/CH₂Cl₂) andfurther purified by preparative HPLC to afford 0.03 g of3-(3-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (Yield=11%).¹HNMR (400 MHz, CDCl₃): δ 7.30-7.25 (m, 2H), 7.09-7.04 (m, 2H),7.01-6.90 (m, 5H), 4.14 (t, J=4.8 Hz, 2H), 3.20 (d, J=10.4 Hz, 1H),3.02-2.93 (m, 3H), 2.87-2.80 (m, 2H), 2.41-2.35 (m, 1H), 1.96-1.83 (m,1H), 1.49 (s, 3H); ESI+MS: m/z: 316 ([M+H]⁺).

Example-54:3-methyl-1-(2-phenoxyethyl)-3-(4-(trifluoromethyl)phenoxy)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.1 g, 0.45 mmol) and1-fluoro-4-(trifluoromethyl)benzene (0.074 g, 0.45 mmol, 1 equiv) washeated in a sealed tube for 16 h using the general methodology of step 2of key intermediate-I. The crude was purified using preparative HPLC toafford 0.03 g of3-methyl-1-(2-phenoxyethyl)-3-(4-(trifluoromethyl)phenoxy)pyrrolidine(Yield=17%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.57 (d, J=9.0 Hz, 2H), 7.26(t, J=8.5 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 6.91-6.89 (m, 3H), 4.05 (t,J=6.0 Hz, 2H), 3.04 (d, J=10.0 Hz, 1H), 2.82-2.74 (m, 4H), 2.66-2.62 (m,1H), 2.23-2.20 (m, 1H), 2.01-1.98 (m, 1H), 1.52 (s, 3H); ESI+MS: m/z:366 ([M+H]⁺).

Example-55:3-methyl-1-(2-phenoxyethyl)-3-(3-(trifluoromethyl)phenoxy)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.20 g, 0.90 mmol) and1-fluoro-3-(trifluoromethyl)benzene (0.148 g, 0.90 mmol, 1 equiv) washeated in a sealed tube for 16 h using the general methodology of step 2of key intermediate-I. Purification using silica gel columnchromatography (1% MeOH/CH₂Cl₂) to afford 0.035 g of3-methyl-1-(2-phenoxyethyl)-3-(3-(trifluoromethyl)phenoxy)pyrrolidine(Yield=10%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.47-7.45 (m, 1H), 7.29-7.22(m, 5H), 6.92-6.89 (m, 3H), 4.05 (t, J=6.0 Hz, 2H), 3.05 (d, J=10.0 Hz,1H), 2.84-2.63 (m, 5H), 2.22-2.20 (m, 1H), 1.97-1.96 (m, 1H), 1.49 (s,3H), ESI+MS: m/z: 366 ([M+H]⁺). The enantiomers of 55 were separatedusing chiral HPLC (method R) and afforded the pure enantiomers 55a and55b.

Example-56: 3-Methyl-1-(2-phenoxyethyl)-3-(2-(trifluoromethyl) phenoxy)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.1 g, 0.45 mmol) and1-fluoro-2-(trifluoromethyl)benzene (0.074 g, 0.45 mmol, 1 equiv) washeated in a sealed tube for 16 h using the general methodology of step 2of key intermediate-I. The crude was purified by preparative HPLCpurification to afford 0.025 g of3-methyl-1-(2-phenoxyethyl)-3-(2-(trifluoromethyl)phenoxy)pyrrolidine(Yield=14%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.58-7.51 (m, 2H), 7.29-7.24(m, 3H), 7.05 (t, J=7.0 Hz, 1H), 6.93-6.89 (m, 3H), 4.05 (t, J=5.5 Hz,2H), 2.99 (d, J=10.0 Hz, 1H), 2.90 (d, J=10.5 Hz, 1H), 2.83-2.75 (m,2H), 2.73-2.69 (m, 2H), 2.28-2.22 (m, 1H), 2.03-1.99 (m, 1H), 1.49 (s,3H); ESI+MS: m/z: 366 ([M+H]⁺).

Example-57: 2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine

To a stirred solution of 3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.1g, 0.45 mmol) in toluene (2 mL) were added potassium tert-butoxide(0.152 g, 1.35 mmol, 3 equiv) and 2-bromo pyridine (0.079 g, 0.45 mmol,1 equiv) under argon atmosphere at room temperature. The reaction washeated at 120° C. in a sealed tube for 16 h. After completion, thevolatiles were removed under reduced pressure; water was added to theresidue and extracted with CH₂Cl₂ The organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure.Purification by preparative HPLC to afford 0.02 g of2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine (Yield=14%).¹H NMR (500 MHz, DMSO-d₆): δ 8.11 (d, J=3.5 Hz, 1H), 7.65 (t, J=7.0 Hz,1H), 7.27 (t, J=7.5 Hz, 2H), 6.93-6.90 (m, 4H), 6.72 (d, J=8.0 Hz, 1H),4.06-4.04 (m, 2H), 3.02-2.95 (m, 2H), 2.79 (br s, 2H), 2.69-2.64 (m,2H), 2.27-2.24 (m, 1H), 2.04-2.00 (m, 1H), 1.66 (s, 3H); ESI+MS: m/z:299 ([M+H]⁺).

Example-58: 3-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine

To a solution of 3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.2 g,0.904 mmol) in DMF (2 mL) were added cesium carbonate (0.589 g, 1.808mmol, 2 equiv) and 3-bromo pyridine (0.157 g, 0.99 mmol, 1.1 equiv)under argon atmosphere at room temperature. The reaction was heated at120° C. for 72 h. After completion, the volatiles were removed underreduced pressure and the residue was diluted with water and extractedwith diethyl ether. The organic layer was separated, dried over sodiumsulfate, filtered, and dried under reduced pressure. Purification bypreparative HPLC to afford 0.013 g of 3-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine (Yield=5%). ¹H NMR (400 MHz, CDCl₃): δ8.40-8.39 (m, 2H), 7.33-7.28 (m, 2H), 6.99-6.92 (m, 3H), 6.84 (d, J=5.2Hz, 2H), 4.14 (t, J=5.6 Hz, 2H), 3.22 (d, J=10.0 Hz, 1H), 2.98-2.92 (m,3H), 2.90-2.81 (m, 1H), 2.79-2.57 (m, 1H), 2.48-2.42 (m, 1H), 2.09-2.03(m, 1H), 1.64 (s, 3H); ESI+MS: m/z: 299 ([M+H]⁺).

Example-59: 4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.1 g, 0.452 mmol) and4-bromopyridine (0.079 g, 0.497 mmol, 1.1 equiv) using the generalmethodology of Example-57. The crude was purified by preparative HPLC toafford 0.015 g of4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine (Yield=10%).¹H NMR (500 MHz, CD₃OD): δ 8.28 (d, J=6.0 Hz, 2H), 7.25 (t, J=7.5 Hz,2H), 6.97 (d, J=6.0 Hz, 2H), 6.91 (t, J=7.5 Hz, 3H), 4.12 (t, J=5.5 Hz,2H), 3.27-3.25 (m, 1H), 2.97-2.86 (m, 4H), 2.79-2.73 (m, 1H), 2.44-2.39(m, 1H), 2.17-2.12 (m, 1H), 1.65 (s, 3H); ESI+MS: m/z: 299 ([M+H]⁺). Theenantiomers of 59 were separated using chiral HPLC (method M) andafforded the pure enantiomers 59a and 59b.

Example-60: 2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyrazine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.1 g, 0.452 mmol) and2-bromopyrazine (0.079 g, 0.497 mmol, 1.1 equiv) using the generalmethodology of Example-57. The crude was purified by preparative HPLC toafford 0.03 g of2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyrazine (Yield=21%).¹H NMR (400 MHz, DMSO-d₆): δ 8.20 (s, 1H), 8.16 (s, 2H), 7.27-7.25 (m,2H), 6.93-6.91 (m, 3H), 4.07-4.04 (m, 2H), 3.07 (br s, 1H), 2.94 (br s,1H), 2.80-2.70 (m, 4H), 2.32-2.27 (m, 1H), 2.09-2.02 (m, 1H), 1.66 (s,3H); ESI+MS: m/z: 300 ([M+H]⁺).

Example-61: 1-(2-(2-Fluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy) piperidine

1-(2-(2-Fluorophenoxy)ethyl)-3-methylpiperidin-3-ol

Title compound was prepared from 3-methylpiperidin-3-ol hydrochloride(0.15 g, 0.98 mmol, 1 equiv) and 1-(2-bromoethoxy)-2-fluorobenzene (0.21g, 0.989 mmol, 1 equiv) using general methodology of Example-1.Purification using silica gel column chromatography (2% MeOH/CH₂Cl₂ aseluent) to afford 0.1 g of1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-one (Yield=39%).

1-(2-(2-fluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl) phenoxy)piperidine

Title compound was prepared from1-(2-(2-fluorophenoxy)ethyl)-3-methylpiperidin-3-ol (0.1 g, 0.39 mmol)and 3-fluoro benzotrifluoride (0.064 g, 0.395 mmol, 1 equiv) using thegeneral methodology of step 2 of key intermediate-I at 100° C. for 24 hin a sealed tube. Purification using silica gel column chromatographyand further purified by prep HPLC to afford 0.02 g of1-(2-(2-fluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl) phenoxy)piperidine (Yield=12%). ¹H NMR (400 MHz, CD₃OD): δ 7.37-7.31 (m, 4H),7.10-7.04 (m, 3H), 6.94-6.89 (m, 1H), 4.19-4.13 (m, 2H), 2.94 (d, J=12.0Hz, 1H), 2.86-2.76 (m, 3H), 2.41-2.31 (m, 2H), 2.08-2.00 (m, 1H),1.94-1.91 (m, 1H), 1.65-1.50 (m, 2H), 1.26 (s, 3H); ESI+MS: m/z: 398([M+H]⁺).

Example-62:1-(2-(2,5-Difluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine

1-(2-(2,5-Difluorophenoxy)ethyl)-3-methylpiperidin-3-ol

Title compound was prepared from 3-methylpiperidin-3-ol hydrochloride(0.3 g, 2.60 mmol) and 2-(2-bromoethoxy)-1,4-difluorobenzene (0.679 g,2.87 mmol, 1.1 equiv) using the general methodology of Example-1.Purification using silica gel column chromatography (5% MeOH in CH₂Cl₂)to afford 0.25 g of1-(2-(2,5-difluorophenoxy)ethyl)-3-methylpiperidin-3-ol (Yield=35.4%).

1-(2-(2,5-difluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine

Title compound was prepared from1-(2-(2,5-difluorophenoxy)ethyl)-3-methylpiperidin-3-ol (0.25 g, 0.92mmol) and 1-fluoro-3-(trifluoromethyl)benzene (0.16 g, 1.02 mmol, 1.1equiv) using the general methodology of Example-61. Purification usingsilica gel column chromatography (2% MeOH/CH₂Cl₂ as eluent) to afford0.015 g of1-(2-(2,5-difluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine(Yield=4%). ¹H NMR (400 MHz, CD₃OD): δ 7.38-7.36 (m, 2H), 7.35-7.31 (m,2H), 7.10-7.04 (m, 1H), 6.91-6.86 (m, 1H), 6.66-6.60 (m, 1H), 4.17-4.11(m, 2H), 2.93-2.76 (m, 4H), 2.40-2.30 (m, 2H), 2.08-2.01 (m, 1H),1.99-1.90 (m, 1H), 1.64-1.51 (m, 2H), 1.29 (s, 3H); ESI+MS: m/z: 416([M+H]⁺).

Example-63: 1-(2-(2-Chlorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy) piperidine

1-(2-(2-Chlorophenoxy)ethyl)-3-methylpiperidin-3-ol

Title compound was prepared from 3-methylpiperidin-3-ol hydrochloride(0.3 g, 2.60 mmol) and 1-(2-bromoethoxy)-2-chlorobenzene (0.675 g, 2.87mmol, 1.1 equiv) using the general methodology of Example-1.Purification using silica gel column chromatography (5% MeOH in CH₂Cl₂as eluent) to afford 0.35 g of1-(2-(2-chlorophenoxy)ethyl)-3-methylpiperidin-3-ol (Yield=50%).

1-(2-(2-Chlorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine

Title compound was prepared from1-(2-(2-chlorophenoxy)ethyl)-3-methylpiperidin-3-ol (0.35 g, 1.29 mmol)and 1-fluoro-3-(trifluoromethyl)benzene (0.23 g, 1.42 mmol, 1.1 equiv)using the general methodology of Example-61. Purification using silicagel and further purified by preparative HPLC to afford 0.02 g of1-(2-(2-chlorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine(Yield=4%). ¹H NMR (400 MHz, CD₃OD): δ 7.36-7.29 (m, 5H), 7.27-7.22 (m,1H), 7.03 (d, J=8.4 Hz, 1H), 6.91 (t, J=7.6 Hz, 1H), 4.21-4.12 (m, 2H),3.06-3.03 (m, 1H), 2.91-2.80 (m, 3H), 2.44-2.34 (m, 2H), 2.08-1.91 (m,2H), 1.65-1.49 (m, 2H), 1.29 (s, 3H); ESI+MS: m/z: 414 ([M+H]⁺).

Example-64: 1-(2-(2-fluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy) pyrrolidine

1-(2-(2-Fluorophenoxy)ethyl)-3-methylpyrrolidin-3-ol

Title compound was prepared from 3-methylpyrrolidin-3-ol hydrochloride(0.5 g, 3.63 mmol) and 1-(2-bromoethoxy)-2-fluorobenzene (0.87 g, 4.0mmol, 1.1 equiv) using the general methodology of Example-1.Purification using silica gel column chromatography (5% MeOH/CH₂Cl₂ aseluent) to afford 0.38 g of1-(2-(2-fluorophenoxy)ethyl)-3-methylpyrrolidin-3-ol (Yield=44%).

1-(2-(2-Fluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)pyrrolidine

Title compound was prepared from1-(2-(2-fluorophenoxy)ethyl)-3-methylpyrrolidin-3-ol (0.38 g, 1.58 mmol)and 3-fluoro benzotrifluoride (0.28 g, 1.74 mmol, 1.1 equiv) using thegeneral methodology of Example-61. Purification using silica gel columnchromatography and further purified by preparative HPLC to afford 0.06 gof1-(2-(2-fluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)pyrrolidine(Yield=9%). ¹H NMR (500 MHz, CD₃OD): δ 7.45 (t, J=8.0 Hz, 1H), 7.27-7.21(m, 3H), 7.12-7.08 (m, 3H), 6.95-6.93 (m, 1H), 4.22 (t, J=5.5 Hz, 2H),3.05-2.97 (m, 3H), 2.86-2.81 (m, 3H), 2.42-2.39 (m, 1H), 2.08-2.05 (m,1H), 1.58 (s, 3H); ESI+MS: m/z: 384 ([M+H]⁺).

Example-65: 1-(2-(2-Chlorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy) pyrrolidine

1-(2-(2-Chlorophenoxy)ethyl)-3-methylpyrrolidin-3-ol

Title compound was prepared from 3-methylpyrrolidin-3-ol hydrochloride(0.5 g, 3.63 mmol) and 1-(2-bromoethoxy)-2-chlorobenzene (0.94 g, 4.0mmol, 1.1 equiv) using the general methodology of Example-1.Purification using silica gel column chromatography (5% MeOH/CH₂Cl₂ aseluent) to afford 0.5 g of1-(2-(2-chlorophenoxy)ethyl)-3-methylpyrrolidin-3-ol (Yield=54%).

1-(2-(2-chlorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl) phenoxy)pyrrolidine

Title compound was prepared from1-(2-(2-chlorophenoxy)ethyl)-3-methylpyrrolidin-3-ol (0.5 g, 1.95 mmol)and 3-fluoro benzotrifluoride (0.35 g, 2.15 mmol, 1.1 equiv) using thegeneral methodology of Example-61. Purification using silica gel columnchromatography (2% MeOH/CH₂Cl₂ as eluent) to afford 0.12 g of1-(2-(2-chlorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)pyrrolidine(Yield=14%). ¹H NMR (400 MHz, CD₃OD): δ 7.42 (t, J=8.0 Hz, 1H), 7.35(dd, J=8.0, 1.6 Hz, 1H), 7.27-7.20 (m, 4H), 7.06 (d, J=8.0 Hz, 1H), 6.92(t, J=7.6 Hz, 1H), 4.21 (t, J=5.2 Hz, 2H), 3.38-3.35 (m, 1H), 3.09-2.96(m, 3H), 2.90-2.80 (m, 2H), 2.42-2.35 (m, 1H), 2.08-2.01 (m, 1H), 1.57(s, 3H); ESI+MS: m/z: 400 ([M+H]⁺).

Example-66:1-(2-(2,5-difluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)pyrrolidine

1-(2-(2,5-Difluorophenoxy)ethyl)-3-methylpyrrolidin-3-ol

Title compound was prepared from 3-methylpyrrolidin-3-ol hydrochloride(0.5 g, 3.63 mmol) and 2-(2-bromoethoxy)-1,4-difluorobenzene (0.94 g,4.0 mmol, 1.1 equiv) using the general methodology of Example-1.Purification using silica gel column chromatography (5% MeOH in CH₂Cl₂as eluent) to afford 0.5 g of1-(2-(2,5-difluorophenoxy)ethyl)-3-methylpyrrolidin-3-ol (Yield=53%).

1-(2-(2,5-difluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy) pyrrolidine

Title compound was prepared from1-(2-(2,5-difluorophenoxy)ethyl)-3-methylpyrrolidin-3-ol (0.2 g, 0.77mmol) and 1-fluoro-3-(trifluoromethyl)benzene (0.14 g, 0.85 mmol, 1.1equiv) using the general methodology of Example-61. Purification usingsilica gel column chromatography and further purified by preparativeHPLC to afford1-(2-(2,5-difluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)pyrrolidine(Yield=0.06 g, 18%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.47 (t, J=8.5 Hz,1H), 7.30-7.20 (m, 4H), 7.15-7.11 (m, 1H), 6.76-6.72 (m, 1H), 4.15 (t,J=6.0 Hz, 2H), 3.07 (d, J=10.0 Hz, 1H), 2.88-2.78 (m, 3H), 2.73-2.63 (m,2H), 2.24-2.19 (m, 1H), 1.99-1.94 (m, 1H), 1.49 (s, 3H); ESI+MS: m/z:402 ([M+H]⁺).

Example-67:4-methyl-4-phenoxy-1-(2-(3-(trifluoromethyl)phenoxy)ethyl)piperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.15 g, 0.65 mmol) and1-(2-bromoethoxy)-3-(trifluoromethyl)benzene (0.17 g, 0.65 mmol) usingthe general methodology of Example-1. Purification using silica gelcolumn chromatography (2% MeOH/CH₂Cl₂ as eluent) to afford 0.11 g of4-methyl-4-phenoxy-1-(2-(3-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=43%). ¹H NMR (400 MHz, CD₃OD): δ 7.47 (t, J=8.0 Hz, 1H),7.28-7.20 (m, 5H), 7.06-6.99 (m, 3H), 4.22 (t, J=5.6 Hz, 2H), 2.92 (t,J=5.6 Hz, 2H), 2.78 (s, 4H), 2.03 (d, J=12.8 Hz, 2H), 1.79-1.72 (m, 2H),1.28 (s, 3H); ESI+MS: m/z 380 ([M+H]⁺).

Example-68: 1-(2-Bromoethoxy)-4-(trifluoromethyl)benzene

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.15 g, 0.659 mmol) and1-(2-bromoethoxy)-4-(trifluoromethyl)benzene (0.177 g, 0.659 mmol, 1equiv) using the general methodology of Example-1. Purification usingsilica gel column chromatography (2% MeOH/CH₂Cl₂ as eluent) to afford0.52 g of 1-(2-bromoethoxy)-4-(trifluoromethyl)benzene (Yield=53%). ¹HNMR (500 MHz, CD₃OD): δ 7.60 (d, J=8.5 Hz, 2H), 7.28 (t, J=15.5 Hz, 2H),7.12-7.01 (m, 5H), 4.25 (t, J=5.5 Hz, 2H), 2.95-2.94 (m, 2H), 2.82-2.80(m, 4H), 2.07-2.04 (m, 2H), 1.80-1.74 (m, 2H), 1.30 (s, 3H); ESI+MS: m/z380 ([M+H]⁺).

Example-69: 4-methyl-4-phenoxy-1-(2-(o-tolyloxy)ethyl)piperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.1 g, 0.439 mmol) and 1-(2-bromoethoxy)-2-methylbenzene(0.094 g, 0.439 mmol, 1 equiv) using the general methodology ofExample-1. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) to afford 0.1 g of4-methyl-4-phenoxy-1-(2-(o-tolyloxy)ethyl)piperidine (Yield=68%). ¹H NMR(400 MHz, CD₃OD): δ 7.28-7.24 (m, 2H), 7.14-7.10 (m, 2H), 7.03-6.99 (m,3H), 6.89 (d, J=8.0 Hz, 1H), 6.83 (t, J=7.6 Hz, 1H), 4.18 (t, J=5.6 Hz,2H), 2.99-2.96 (m, 2H), 2.87-2.85 (m, 4H), 2.20 (s, 3H), 2.07-2.02 (m,2H), 1.80-1.71 (m, 2H), 1.29 (s, 3H); ESI+MS: m/z 326 ([M+H]⁺).

Example-70: 1-(2-(2-Ethylphenoxy)ethyl)-4-methyl-4-phenoxypiperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.2 g, 0.87 mmol) and 1-(2-bromoethoxy)-2-ethylbenzene(0.2 g, 0.87 mmol, 1.0 equiv) using the general methodology ofExample-1. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) to afford 0.08 g of1-(2-(2-ethylphenoxy)ethyl)-4-methyl-4-phenoxypiperidine (Yield=26%). ¹HNMR (400 MHz, CD₃OD): δ 7.26 (t, J=7.6 Hz, 2H), 7.13-7.11 (m, 2H),7.07-6.99 (m, 3H), 6.92-6.84 (m, 2H), 4.18 (t, J=5.6 Hz, 2H), 2.96 (t,J=5.2 Hz, 2H), 2.86-2.84 (m, 4H), 2.66-2.61 (m, 2H), 2.06-2.02 (m, 2H),1.79-1.70 (m, 2H), 1.29 (s, 3H), 1.16 (t, 3H, J=7.6 Hz); ESI+MS: m/z:340 ([M+H]⁺).

Example-71: 1-(2-(2-isopropylphenoxy)ethyl)-4-methyl-4-phenoxypiperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.15 g, 0.65 mmol) and1-(2-bromoethoxy)-2-isopropylbenzene (0.16 g, 0.65 mmol, 1.0 equiv)using the general methodology of Example-1. Purification using silicagel column chromatography (2% MeOH in CH₂Cl₂ as eluent) to afford 0.12 g1-(2-(2-isopropylphenoxy)ethyl)-4-methyl-4-phenoxypiperidine(Yield=51%). ¹H NMR (400 MHz, CD₃OD): δ 7.28-7.24 (m, 2H), 7.19 (d,J=7.2 Hz, 1H), 7.13 (t, J=7.2 Hz, 1H), 7.07-7.03 (m, 1H), 7.01-6.99 (m,2H), 6.92-6.87 (m, 2H), 4.17 (t, J=5.6 Hz, 2H), 3.40-3.30 (m, 1H), 2.95(t, J=5.6 Hz, 2H), 2.84-2.81 (m, 4H), 2.06-2.01 (m, 2H), 1.78-1.71 (m,2H), 1.29 (s, 3H), 1.19 (d, J=6.8 Hz, 6H); ESI+MS: m/z 354 [M+H]⁺.

Example-72: 1-(2-(2-Methoxyphenoxy)ethyl)-4-methyl-4-phenoxypiperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.1 g, 0.439 mmol) and 1-(2-bromoethoxy)-2-methoxybenzene(0.1 g, 0.43 mmol, 1.0 equiv) using the general methodology ofExample-1. Purification using silica gel column chromatography 2% MeOHin CH₂Cl₂ as eluent) to afford 0.11 g of1-(2-(2-methoxyphenoxy)ethyl)-4-methyl-4-phenoxypiperidine (Yield=73%).¹H NMR (400 MHz, CD₃OD): δ 7.29-7.24 (m, 2H), 7.07-6.86 (m, 7H), 4.18(t, J=5.6 Hz, 2H), 3.82 (s, 3H), 2.98-2.95 (m, 2H), 2.88-2.86 (m, 4H),2.06-2.03 (m, 2H), 1.80-1.73 (m, 2H), 1.29 (s, 3H); ESI+MS: m/z 342([M+H]⁺).

Example-73:2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)pyridine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.1 g, 0.43 mmol) and 1-(2-chloroethyl)pyridin-2(1H)-one(0.07 g, 0.48 mmol, 1.1 equiv) using the general methodology ofExample-1. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) to afford 0.08 g of1-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethyl)pyridin-2(1H)-one(Yield=58%). ¹H NMR (400 MHz, CD₃OD): δ 7.65-7.63 (m, 1H), 7.54-7.49 (m,1H), 7.28-7.23 (m, 2H), 7.06-6.97 (m, 3H), 6.55-6.52 (m, 1H), 6.37 (dt,J=8.0, 1.2 Hz, 1H), 4.15 (t, J=6.8 Hz, 2H), 2.77-2.66 (m, 6H), 2.01-1.96(m, 2H), 1.72-1.65 (m, 2H), 1.26 (s, 3H); ESI+MS: m/z 313 ([M+H]⁺).

Example-74: 4-Methyl-1-(2-(naphthalen-2-yloxy)ethyl)-4-phenoxypiperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.15 g, 0.65 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) to afford 0.12 g of4-methyl-1-(2-(naphthalen-2-yloxy)ethyl)-4-phenoxypiperidine(Yield=48%). ¹H NMR (400 MHz, CD₃OD): δ 8.25 (dd, J=8.0, 4.0 Hz, 1H),7.80-7.78 (m, 1H), 7.49-7.35 (m, 4H), 7.28-7.23 (m, 2H), 7.06-6.99 (m,3H), 6.94-6.92 (m, 1H), 4.37 (t, J=5.6 Hz, 2H), 3.11 (t, J=5.2 Hz, 2H),2.96-2.87 (m, 4H), 2.09-2.04 (m, 2H), 1.81-1.71 (m, 2H), 1.29 (s, 3H);ESI+MS: m/z 362 [(M+H]⁺).

Example-75:1-(2-(4-Fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methyl-4-phenoxypiperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.1 g, 0.43 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) to afford 0.08 g of1-(2-(4-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methyl-4-phenoxypiperidine(Yield=45%). ¹H NMR (400 MHz, CD₃OD): δ 7.37-7.31 (m, 2H), 7.28-7.20 (m,3H), 7.07-7.03 (m, 1H), 7.01-6.98 (m, 2H), 4.26 (t, J=5.6 Hz, 2H), 2.95(t, J=5.2 Hz, 2H), 2.86-2.80 (m, 4H), 2.04-1.99 (m, 2H), 1.77-1.70 (m,2H), 1.28 (s, 3H); ESI+MS: m/z 398 [(M+H)⁺].

Example-76:1-(2-(5-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methyl-4-phenoxypiperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.1 g, 0.43 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) to afford 0.07 g of1-(2-(5-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methyl-4-phenoxypiperidine(Yield=37%). ¹H NMR (400 MHz, CD₃OD): δ 7.62-7.58 (m, 1H), 7.27-7.23 (m,2H), 7.06-6.97 (m, 4H), 6.81-6.76 (m, 1H), 4.25 (t, J=5.2 Hz, 2H), 2.93(t, J=5.6 Hz, 2H), 2.84-2.74 (m, 4H), 2.03-1.98 (m, 2H), 1.75-1.68 (m,2H), 1.26 (s, 3H); ESI+MS: m/z 398 ([M+H]⁺).

Example-77:1-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.1 g, 0.43 mmol) and1-(2-bromoethyl)-3-(trifluoromethyl)pyridin-2(1H)-one (0.17 g, 0.65mmol, 1.5 equiv) using the general methodology of Example-1.Purification using silica gel column chromatography (2% MeOH/CH₂Cl₂ aseluent) to afford 0.04 g of1-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one(Yield=23%). ¹H NMR (400 MHz, CD₃OD): δ 7.91 (t, J=6.4 Hz, 2H), 7.25 (t,J=7.6 Hz, 2H), 7.06-6.98 (m, 3H), 6.44-6.41 (m, 1H), 4.18 (t, J=6.4 Hz,2H), 2.76-2.63 (m, 6H), 1.99-1.96 (m, 2H), 1.70-1.63 (m, 2H), 1.26 (s,3H); ESI+MS: m/z 381 ([M+H]⁺).

Example-78:3-Methyl-3-phenoxy-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octane

tert-butyl3-methyl-3-(4-nitrophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

Title compound was prepared fromtert-butyl(1R,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate(0.9 g, 3.73 mmol) using the general methodology of step 2 of keyintermediate-I at 80° C. 16 h. Purification using silica gel columnchromatography (10% EtOAc/Hexanes as eluent) to afford 0.8 g oftert-butyl3-methyl-3-(4-nitrophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate(Yield=59%).

tert-butyl(1R,5S)-3-(4-aminophenoxy)-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate

Title compound was prepared from tert-butyl3-methyl-3-(4-nitrophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (0.8g, 2.2 mmol) using general methodology of step 3 of key intermediate-Iat 80° C. for 16 h. Purification using silica gel column chromatography(15% EtOAc in Hexane as eluent) to afford 0.5 g of tert-butyl(1R,5S)-3-(4-aminophenoxy)-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate(Yield=68%).

tert-butyl(1R,5S)-3-methyl-3-phenoxy-8-azabicyclo[3.2.1]octane-8-carboxylate

Title compound was prepared from tert-butyl(1R,5S)-3-(4-aminophenoxy)-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate(0.5 g, 1.5 mmol) using the general methodology of step 1 of keyintermediate-VI at 80° C. for 3 h. Purification using silica gel columnchromatography (5% EtOAc in Hexane as eluent) to afford 0.3 g oftert-butyl(1R,5S)-3-methyl-3-phenoxy-8-azabicyclo[3.2.1]octane-8-carboxylate(Yield=62%).

(1R,5S)-3-methyl-3-phenoxy-8-azabicyclo[3.2.1]octane hydrochloride

Title compound was prepared from tert-butyl(1R,5S)-3-methyl-3-phenoxy-8-azabicyclo[3.2.1]octane-8-carboxylate (0.3g, 0.94 mmol) using general methodology of step 2 of key intermediate-VIto afford 0.2 g of 4-benzylpiperidin-4-ol hydrochloride (Yield=83%).

3-Methyl-3-phenoxy-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octane

Title compound was prepared from 4-benzylpiperidin-4-ol hydrochloride(0.2 g, 0.78 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (2% MeOH in CH₂Cl₂as eluent) to afford 0.32 g of2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine(Yield=39%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.63-7.59 (m, 2H), 7.29-7.24(m, 3H), 7.08 (t, J=7.2 Hz, 1H), 6.96-6.94 (m, 3H), 4.19-4.17 (m, 2H),3.28-3.26 (m, 2H), 2.73-2.70 (m, 2H), 2.13-2.09 (m, 2H), 1.97-1.95 (m,2H), 1.80-1.77 (m, 4H), 1.23 (s, 3H); ESI+MS: m/z: 406 ([M+H]⁺).

Example-79:4-methyl-1-(2-methyl-1-(2-(trifluoromethyl)phenoxy)propan-2-yl)-4-phenoxypiperidine

Methyl 2-methyl-2-(4-methyl-4-phenoxypiperidin-1-yl)propanoate

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.5 g, 2.19 mmol, 1 equiv) and methyl2-bromo-2-methylpropanoate (0.43 g, 2.41 mmol, 1.1 equiv) using thegeneral methodology of Example-1. Purification using silica gel columnchromatography (2% MeOH in CH₂Cl₂ as eluent) to afford 0.4 g of2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine(Yield=62%).

2-methyl-2-(4-methyl-4-phenoxypiperidin-1-yl)propan-1-ol

To a stirred solution of methyl2-methyl-2-(4-methyl-4-phenoxypiperidin-1-yl)propanoate (0.4 g, 1.37mmol) in THF (20 mL) was added LiAlH₄ (0.07 mg, 2.08 mmol, 1.5 equiv) at0° C. The reaction mixture was warmed to room temperature and stirredfor 2 h. After completion, the reaction was quenched with EtOAc,Na₂SO_(4 (aq)) and extracted with EtOAc. The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to afford0.3 g of 2-methyl-2-(4-methyl-4-phenoxypiperidin-1-yl)propan-1-ol(Yield=78%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.29-7.24 (m, 2H), 7.05-7.01(m, 1H), 6.97 (d, J=8.8 Hz, 2H), 4.14 (br s, 1H), 3.26 (s, 2H),2.68-2.62 (m, 2H), 2.57-2.54 (m, 2H), 1.87-1.82 (m, 2H), 1.59-1.53 (m,2H), 1.21 (s, 3H), 0.94 (s, 6H); ESI+MS: m/z: 264 ([M+H]⁺).

Example-80:4-methyl-1-(2-methyl-1-(2-(trifluoromethyl)phenoxy)propan-2-yl)-4-phenoxypiperidine

Title compound was prepared from2-methyl-2-(4-methyl-4-phenoxypiperidin-1-yl)propan-1-ol (0.1 g, 0.38mmol) and 1-fluoro-2-(trifluoromethyl)benzene (0.09 mg, 0.57 mmol, 1.5equiv) using the general methodology of Example-61 and heated for 24 h.Purification using silica gel column chromatography further purified bypreparative HPLC to afford 0.07 g of4-methyl-1-(2-methyl-1-(2-(trifluoromethyl)phenoxy)propan-2-yl)-4-phenoxypiperidine(Yield=45%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.62-7.58 (m, 2H), 7.29-7.24(m, 3H), 7.09-7.01 (m, 2H), 6.97-6.94 (m, 2H), 3.96 (s, 2H), 2.79-2.73(m, 2H), 2.67-2.64 (m, 2H), 1.87-1.83 (m, 2H), 1.60-1.53 (m, 2H), 1.21(s, 3H), 1.14 (s, 6H); ESI+MS: m/z: 408 ([M+H]⁺).

Example-81: 2-(4-Methyl-4-phenoxypiperidin-1-yl)propan-1-ol

Methyl 2-(4-methyl-4-phenoxypiperidin-1-yl)propanoate

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.3 g, 1.31 mmol) and methyl 2-bromo-2-methylpropanoate(0.24 g, 1.44 mmol, 1.1 equiv) using the general methodology ofExample-1. Purification using silica gel column chromatography (2% MeOHin CH₂Cl₂ as eluent) to afford 0.35 g of methyl2-(4-methyl-4-phenoxypiperidin-1-yl)propanoate (Yield=96%).

2-(4-Methyl-4-phenoxypiperidin-1-yl)propan-1-ol

To a solution of methyl 2-(4-methyl-4-phenoxypiperidin-1-yl)propanoate(0.35 g, 1.26 mmol) in THF (10 mL) was added LiAlH₄ (0.07 mg, 1.89 mmol,1.5 equiv) at 0° C. The reaction mixture was warmed to room temperatureand stirred for 2 h. After completion, the reaction mass was quenchedwith EtOAc and aq. Na₂SO₄ and extracted with EtOAc. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford 0.25 g of 2-(4-methyl-4-phenoxypiperidin-1-yl)propan-1-ol(Yield=79%).

Example-82:4-Methyl-4-phenoxy-1-(1-(2-(trifluoromethyl)phenoxy)propan-2-yl)piperidine

Title compound was prepared from2-(4-methyl-4-phenoxypiperidin-1-yl)propan-1-ol (0.2 g, 0.8 mmol) and1-fluoro-2-(trifluoromethyl)benzene (0.19 g, 1.2 mmol, 1.5 equiv) usingthe general methodology of Example-61. Purification using silica gelcolumn chromatography further purified by preparative HPLC to afford0.016 g of4-methyl-4-phenoxy-1-(1-(2-(trifluoromethyl)phenoxy)propan-2-yl)piperidine(yield=19%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.62-7.59 (m, 2H), 7.29-7.25(m, 3H), 7.09-7.03 (m, 2H), 6.97 (d, J=8.0 Hz, 2H), 4.20-4.18 (m, 1H),4.03-4.00 (m, 1H), 3.03-3.01 (m, 1H), 2.80-2.73 (m, 2H), 2.60-2.57 (m,2H), 1.86-1.84 (m, 2H), 1.60-1.55 (m, 2H), 1.22 (s, 3H), 1.11 (d, J=6.5Hz, 3H); ESI+MS: m/z 394 ([M+H]⁺).

Example-83: 2,4,6-Trimethyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl) piperidine

tert-butyl 4-hydroxy-2,4,6-trimethylpiperidine-1-carboxylate

Title compound was prepared from tert-butyl2,6-dimethyl-4-oxopiperidine-1-carboxylate (2 g, 8.8 mmol) using thegeneral methodology of step 1 of key intermediate-I for 4 h.Purification using silica gel column chromatography (12% EtOAc/Hexanesas eluent) to afford 0.86 g of tert-butyl4-hydroxy-2,4,6-trimethylpiperidine-1-carboxylate (Yield=40%).

tert-butyl 2,4,6-trimethyl-4-(4-nitrophenoxy)piperidine-1-carboxylate

Title compound was prepared from tert-butyl4-hydroxy-2,4,6-trimethylpiperidine-1-carboxylate (0.85 g, 3.49 mmol)and 4-fluoro nitrobenzene (0.74 g, 5.24 mmol, 1.5 equiv) using thegeneral methodology of step 2 of key intermediate-I. Purification usingsilica gel column chromatography (7% EtOAc in Hexane as eluent) toafford 0.3 g of tert-butyl2,4,6-trimethyl-4-(4-nitrophenoxy)piperidine-1-carboxylate (Yield=24%).

tert-butyl 4-(4-aminophenoxy)-2,4,6-trimethylpiperidine-1-carboxylate

Title compound was prepared from tert-butyl2,4,6-trimethyl-4-(4-nitrophenoxy)piperidine-1-carboxylate (0.3 g, 0.82mmol) using the general methodology of step 3 of key intermediate-I toafford 0.23 g of tert-butyl4-(4-aminophenoxy)-2,4,6-trimethylpiperidine-1-carboxylate (Yield: 84%).

tert-butyl 2,4,6-trimethyl-4-phenoxypiperidine-1-carboxylate

Title compound was prepared from tert-butyl4-(4-aminophenoxy)-2,4,6-trimethylpiperidine-1-carboxylate (0.23 g, 0.68mmol) using the general methodology of step 1 of key intermediate-VI at80° C. for 6 h. Purification using silica gel column chromatography (7%EtOAc in Hexane as eluent) to afford 0.13 g of tert-butyl2,4,6-trimethyl-4-phenoxypiperidine-1-carboxylate (Yield=59%).

2,4,6-Trimethyl-4-phenoxypiperidine hydrochloride

To a solution of tert-butyl 2, 4,6-trimethyl-4-phenoxypiperidine-1-carboxylate (0.12 g, 0.36 mmol) indiethyl ether (2 mL) was added 4 M HCl in 1,4-Dioxane (1 mL) at roomtemperature. The reaction mixture was stirred at room temperature for 16h. After completion, the reaction mass was concentrated under reducedpressure to obtain the 2, 4, 6-trimethyl-4-phenoxypiperidinehydrochloride (Quantitative).

2,4,6-trimethyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

Title compound was prepared from 2,4,6-trimethyl-4-phenoxypiperidinehydrochloride (0.1 g, 0.39 mmol) and1-(2-bromoethoxy)-2-(trifluoromethyl)benzene (0.10 g, 0.39 mmol, 1equiv) using the general methodology of Example-1. Purification usingsilica gel column chromatography (2% MeOH in CH₂Cl₂ as eluent) to afford0.019 g of 2, 4,6-trimethyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=11%). ¹H NMR (400 MHz, CD₃OD): δ 7.59-7.55 (m, 2H), 7.29-7.18 (m,3H), 7.08-6.97 (m, 4H), 4.22-4.17 (m, 2H), 3.48-3.43 (m, 2H), 3.25-3.12(m, 2H), 2.05 (d, J=14.4 Hz, 1H), 1.98-1.91 (m, 2H), 1.50-1.44 (m, 1H),1.39-1.35 (m, 3H), 1.25 (s, 3H), 1.24-1.19 (m, 3H); ESI+MS: m/z 408([M+H]⁺).

Example-84: 3-(2-Methoxyphenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

3-(2-Methoxy-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.70 g, 3.76 mmol) and1-fluoro-2-methoxy-4-nitrobenzene (0.59 g, 3.48 mmol, 1.1 equiv) usingthe general methodology of step 2 of key intermediate-I. Purificationusing silica gel column chromatography (5% MeOH/CH₂Cl₂ as eluent) toafford 0.95 g of3-(2-methoxy-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(Yield=81%). ESI+MS: m/z 373 ([M+H]⁺).

3-Methoxy-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

Title compound was prepared from3-(2-methoxy-4-nitrophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine(0.55 g, 1.47 mmol) using the general methodology of step 3 of keyintermediate-I to afford 0.48 g of3-methoxy-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(Yield=95%).

3-(2-Methoxyphenoxy)-3 methyl-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methoxy-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(0.25 g, 0.73 mmol) using the general methodology of Example-51. Thecrude was purified by preparative HPLC to afford 0.015 g of3-(2-methoxyphenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine (Yield=6%).¹H NMR (400 MHz, CD₃OD): δ 7.28-7.22 (m, 2H), 7.03-6.89 (m, 6H),6.85-6.81 (m, 1H), 4.12 (t, J=5.6 Hz, 2H), 3.78 (s, 3H), 3.24 (d, J=10.8Hz, 1H), 3.01-2.89 (m, 3H), 2.85-2.76 (m, 2H), 2.40-2.34 (m, 1H),1.94-1.87 (m, 1H), 1.44 (s, 3H); ESI+MS: m/z 328 ([M+H]⁺).

Example-85: 3-Methyl-1-(2-phenoxyethyl)-3-(o-tolyloxy)pyrrolidine

3-Methyl-3-(2-methyl-4-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine

Title compound was prepared from3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.50 g, 2.26 mmol) and1-fluoro-2-methyl-4-nitrobenzene (0.28 g, 2.48 mmol, 1.1 equiv) usingthe general methodology of step 2 of key intermediate-I. Purificationusing silica gel column chromatography (5% MeOH/CH₂Cl₂ as eluent) toafford 0.45 g of3-methyl-3-(2-methyl-4-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine(Yield=48%). ESI+MS: m/z 357 ([M+H]⁺).

3-Methyl-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline

Title compound was prepared from3-methyl-3-(2-methyl-4-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine (0.40g, 1.12 mmol) using the general methodology of step 3 of keyintermediate-I to afford 0.34 g of3-methyl-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(Yield=88%). ESI+MS: m/z 327 ([M+H]⁺).

3-Methyl-1-(2-phenoxyethyl)-3-(o-tolyloxy)pyrrolidine

Title compound was prepared from3-methyl-4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline(0.05 g, 0.15 mmol) using the general methodology of Example-51. Thecrude was purified by preparative HPLC to afford 0.009 g of3-methyl-1-(2-phenoxyethyl)-3-(o-tolyloxy)pyrrolidine (Yield=17%). ¹HNMR (500 MHz, CD₃OD): δ 7.28 (t, J=7.5 Hz, 2H), 7.14-7.06 (m, 2H),6.95-6.92 (m, 4H), 6.85 (t, J=7.5 Hz, 1H), 4.15 (t, J=5.5 Hz, 2H), 3.28(d, J=10.8 Hz, 1H), 3.01-2.86 (m, 5H), 2.47-2.42 (m, 1H), 2.19 (s, 3H),2.10-2.05 (m, 1H), 1.55 (s, 3H); ESI+MS: m/z 312 ([M+H]⁺).

Example-86:4-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.12 g) and 1-(2-bromoethoxy)-2-fluorobenzene (0.14 g, 0.63 mmol, 1.2equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC purification to afford 0.025 g of4-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-4-methylpiperidine(Yield=13%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.31 (d, J=8.8 Hz, 2H),7.21-7.16 (m, 2H), 7.01 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H),6.95-6.90 (m, 1H), 4.14 (t, J=6.0 Hz, 2H), 2.71-2.89 (m, 2H), 2.57-2.54(m, 4H), 1.87-1.84 (m, 2H), 1.65-1.61 (m, 2H), 1.24 (s, 3H); ESI+MS: m/z364 ([M+H]⁺).

Example-87: 1-(2-(2-fluorophenoxy)ethyl)-4-methyl-4-phenoxypiperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidine (0.12 g)and 1-(2-bromoethoxy)-2-fluorobenzene (0.14 g, 0.63 mmol, 1.2 equiv)using the general methodology of Example-1. The crude was purified bypreparative HPLC purification to afford 0.025 g of1-(2-(2-fluorophenoxy)ethyl)-4-methyl-4-phenoxypiperidine (Yield=8%). ¹HNMR (400 MHz, DMSO-d₆): δ 7.27 (t, J=7.6 Hz, 2H), 7.21-7.16 (m, 2H),7.11 (t, J=7.6 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 2H),6.95-6.92 (m, 1H), 4.14 (t, J=5.6 Hz, 2H), 2.79-2.54 (m, 2H), 2.57-2.54(m, 4H), 1.89-1.84 (m, 2H), 1.64-1.58 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z330 ([M+H]⁺).

Example-88:4-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.12 g, 0.53 mmol) and 1-(2-bromoethoxy)-2-chlorobenzene (0.15 g, 0.63mmol, 1.2 equiv) using the general methodology of Example-1. The crudewas purified by preparative HPLC purification to afford 0.02 g of4-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-4-methylpiperidine(Yield=9%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.40 (d, J=8.0 Hz, 1H),7.32-7.27 (m, 3H), 7.16 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.94(t, J=7.6 Hz, 1H), 4.16 (t, J=5.6 Hz, 2H), 2.78-2.75 (m, 2H), 2.62-2.58(m, 4H), 1.90-1.84 (m, 2H), 1.64-1.62 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z381 ([M+H]⁺).

Example-89: 1-(2-(2-Chlorophenoxy)ethyl)-4-methyl-4-phenoxypiperidine

Title compound was prepared from 4-phenoxy-4-methylpiperidine (0.12 g,0.53 mmol) and 1-(2-bromoethoxy)-2-chlorobenzene (0.15 g, 0.63 mmol, 1.2equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC purification to afford 0.01 g of1-(2-(2-chlorophenoxy)ethyl)-4-methyl-4-phenoxypiperidine (Yield=5%). ¹HNMR (400 MHz, DMSO-d₆): δ 7.41 (d, J=8.0 Hz, 1H), 7.29-7.25 (m, 3H),7.16 (d, J=8.0 Hz, 1H), 7.04 (t, J=7.2 Hz, 1H), 6.99-6.92 (m, 3H),4.16-4.14 (m, 2H), 2.75-2.71 (m, 2H), 2.67-2.61 (m, 4H), 1.90-1.81 (m,2H), 1.65-1.51 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 346 ([M+H]⁺).

Example-90: 4-(4-Chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl) piperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.12 g, 0.53 mmol) and 1-(2-bromoethoxy)-2-(trifluoromethyl)benzene(0.17 g, 0.63 mmol, 1.2 equiv) using the general methodology ofExample-1. The crude was purified by preparative HPLC purification toafford 0.01 g of4-(4-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=4%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.60 (d, J=8.0 Hz, 2H),7.32-7.26 (m, 3H), 7.08 (d, J=8.0 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H),4.16-4.01 (m, 2H), 2.76-2.73 (m, 2H), 2.57-2.55 (m, 4H), 1.85-1.82 (m,2H), 1.65-1.61 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 414 ([M+H]⁺).

Example-91:4-methyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidine (0.12 g,0.53 mmol) and 1-(2-bromoethoxy)-2-(trifluoromethyl)benzene (0.17 g,0.63 mmol, 1.2 equiv) using the general methodology of Example-1. Thecrude was purified by preparative HPLC purification to afford 0.008 g of4-methyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=4%). ¹H NMR (400 MHz, CD₃OD): δ 7.58 (d, J=7.6 Hz, 2H), 7.29-7.25(m, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.08-7.03 (m, 2H), 7.01-6.99 (m, 2H),4.29 (t, J=5.6 Hz, 2H), 3.00 (t, J=5.6 Hz, 2H), 2.90-2.86 (m, 4H),2.06-2.01 (m, 2H), 1.78-1.71 (m, 2H), 1.28 (s, 3H); ESI+MS: m/z 380([M+H]⁺).

Example-92:6-(2-(3-(4-Chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)benzo[d]oxazole

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidine(0.07 g, 0.33 mmol) and 6-(2-bromoethoxy)benzo[d]oxazole (0.08 g, 0.33mmol, 1 equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC to afford 0.02 g of6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)benzo[d]oxazole(Yield=16%). ¹H NMR (400 MHz, CD₃OD): δ 8.33 (s, 1H), 7.61 (d, J=8.8 Hz,1H), 7.26 (s, 1H), 7.21-7.17 (m, 2H), 7.03 (dd, J=8.8, 2.0 Hz, 1H),6.94-6.90 (m, 2H), 4.18 (t, J=5.6 Hz, 2H), 3.23 (d, J=5.6 Hz, 1H),3.03-2.89 (m, 3H), 2.79-2.72 (m, 2H), 2.38-2.31 (m, 1H), 2.02-1.95 (m,1H), 1.51 (s, 3H); ESI+MS: m/z 373 ([M+H])⁺.

Example-93: 1-(2-Phenoxyethyl)-3-phenylpyrrolidin-3-ol

tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate

To a suspension of magnesium (0.98 g, 40.5 mmol, 3 equiv) in dry diethylether (20 mL) was added iodine (catalytic) and bromobenzene (6.36 g,40.5 mmol, 3 equiv) in dry diethyl ether (10 mL) at room temperature andstirred for 30 min. This was added to a stirred solution of tert-butyl3-oxopyrrolidine-1-carboxylate (2.5 g, 13.5 mmol) in dry THF (10 mL) at0° C. and stirred at room temperature for 2 h. After completion, thereaction was quenched with saturated NH₄Cl solution at 0° C. andextracted with EtOAc. The combined organic extract was dried over sodiumsulfate, filtered and concentrated under reduced pressure. Purificationusing silica gel column chromatography (20% EtOAc/hexanes as eluent) toafford 1.5 g of tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate(Yield=42%).

3-Phenylpyrrolidin-3-ol hydrochloride

To a solution of tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate(1.5 g, 5.7 mmol) in MeOH (5 mL) was added 2 M HCl in diethyl ether (13mL) under argon atmosphere at 0° C. The reaction was stirred at roomtemperature for 4 h. After completion, the solvent was removed underreduced pressure to afford 1 g of 3-phenylpyrrolidin-3-ol hydrochloride(Yield=88%).

1-(2-Phenoxyethyl)-3-phenylpyrrolidin-3-ol

Title compound was prepared from 3-phenylpyrrolidin-3-ol hydrochloride(1 g, 5.01 mmol) and (2-bromoethoxy)benzene (1.2 g, 6.01 mmol, 1.2equiv) using the general methodology of Example-1. Purification usingsilica gel column chromatography (25% EtOAc/hexanes) to afford 1.2 g of1-(2-phenoxyethyl)-3-phenylpyrrolidin-3-ol (Yield=85%). ¹H NMR (400 MHz,DMSO-d₆): δ 7.50 (d, J=8.4 Hz, 2H), 7.31-7.25 (m, 4H), 7.19 (t, J=7.6Hz, 1H), 6.94-6.90 (m, 3H), 5.21 (br s, 1H), 4.08 (t, J=6.0 Hz, 2H),2.99-2.82 (m, 6H), 2.14-1.98 (m, 2H); ESI+MS: m/z 284 ([M+H]⁺).

Example-94: 3-(4-nitrophenoxy)-1-(2-phenoxyethyl)-3-phenylpyrrolidine

Title compound was prepared from1-(2-phenoxyethyl)-3-phenylpyrrolidin-3-ol (1.2 g, 4.23 mmol) and1-fluoro-4-nitrobenzene (0.71 g, 5.08 mmol, 1.2 equiv) 80° C. for 16 husing the general methodology of step 2 of key intermediate-I.Purification using silica gel column chromatography (15% EtOAc/hexanes)to afford 0.80 g of3-(4-nitrophenoxy)-1-(2-phenoxyethyl)-3-phenylpyrrolidine (Yield=47%).¹H NMR (500 MHz, DMSO-d₆): δ 8.04 (d, J=9.5 Hz, 2H), 7.37-7.34 (m, 4H),7.27 (t, J=8.0 Hz, 3H), 6.94-6.90 (m, 3H), 6.80 (d, J=9.5 Hz, 2H), 4.10(d, J=5.5 Hz, 2H), 3.24-3.18 (m, 2H), 2.95-2.85 (m, 4H), 2.57-2.53 (m,1H), 2.44-2.40 (m, 1H); ESI+MS: m/z 405 ([M+H]⁺).

Example-95: 4-((1-(2-phenoxyethyl)-3-phenylpyrrolidin-3-yl)oxy)aniline

To a solution of3-(4-nitrophenoxy)-1-(2-phenoxyethyl)-3-phenylpyrrolidine (0.60 g, 1.48mmol, 1 equiv) in EtOH/H₂O (3:1, 16 mL) was added iron powder (0.41 g,7.42 mmol, 5 equiv) and ammonium chloride (0.39 g, 7.42 mmol, 5 equiv)at room temperature. The reaction mixture was heated at 80° C. for 4 h.After completion, the reaction was filtered through celite pad; andwashed with MeOH. The filtrate was concentrated under reduced pressure;residue was diluted with EtOAc and washed with water. The organic layerwas dried over sodium sulfate, filtered and concentrated under reducedpressure. The obtained solid was triturated with pentane to afforded 0.4g of 4-((1-(2-phenoxyethyl)-3-phenylpyrrolidin-3-yl)oxy)aniline(Yield=72%). ¹H NMR (400 MHz, CD₃OD): δ 7.45-7.39 (m, 5H), 7.35-7.31 (m,2H), 7.01 (t, J=7.6 Hz, 3H), 6.49 (d, J=8.8 Hz, 2H), 6.40 (d, J=6.8 Hz,2H), 4.39-4.20 (m, 2H), 4.24 (d, J=12.0 Hz, 1H), 3.92-3.73 (m, 4H), 3.67(d, J=12.0 Hz, 1H), 2.84-2.80 (m, 1H), 2.77-2.68 (m, 1H), 1.40-1.20 (m,1H), 0.95-0.87 (m, 1H); ESI+MS: m/z 375 ([M+H]⁺).

Example-96: 3-(4-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)piperidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpiperidine(0.13 g, 0.57 mmol) and (2-bromoethoxy)benzene (0.11 g, 0.57 mmol, 1equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC to afford 0.08 g of3-(4-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)piperidine (Yield=39%).¹H NMR (500 MHz, DMSO-d₆): δ 7.27 (t, J=8.0 Hz, 2H), 7.13 (d, J=9.0 Hz,2H), 7.06 (d, J=9.0 Hz, 2H), 6.92-6.89 (m, 3H), 3.99-3.96 (m, 2H),2.72-2.67 (m, 1H), 2.61-2.59 (m, 3H), 2.34-2.29 (m, 1H), 2.15 (d, J=12.0Hz, 1H), 1.83-1.70 (m, 2H), 1.51-1.47 (m, 2H), 1.16 (s, 3H); ESI+MS: 346([M+H]⁺). The enantiomers of 96 were separated using chiral HPLC (methodN) and afforded the pure enantiomers 96a and 96b.

Example-97:3-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-3-methylpiperidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpiperidine(0.08 g, 0.35 mmol) and 1-(2-bromoethoxy)-2-chlorobenzene (0.83 g, 0.35mmol, 1 equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC to afford 0.019 g of3-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-3-methylpiperidine(Yield=14%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.41 (dd, J=7.6, 1.6 Hz, 1H),7.29 (dt, J=8.4, 1.6 Hz, 1H), 7.17-7.13 (m, 3H), 7.08-7.04 (m, 2H), 6.95(dt, J=8.8, 1.2 Hz, 1H), 4.09 (t, J=5.6 Hz, 2H), 2.74-2.66 (m, 4H),2.38-2.32 (m, 1H), 2.25 (d, J=12.0 Hz, 1H), 1.86-1.69 (m, 2H), 1.54-1.48(m, 2H), 1.19 (s, 3H); ESI+MS: m/z: 381 [(M+H)⁺].

Example-98:3-(4-Chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-3-methylpiperidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpiperidine(0.08 g, 0.35 mmol) and 1-(2-bromoethoxy)-2-fluorobenzene (0.078 g, 0.35mmol, 1 equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC to afford 0.019 g of3-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-3-methylpiperidine(Yield=14%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.23-7.07 (m, 7H), 6.94-6.92(m, 1H), 4.09 (t, J=5.6 Hz, 2H), 2.74-2.60 (m, 4H), 2.32-2.28 (m, 1H),2.20 (d, J=12.0 Hz, 1H), 1.85-1.72 (m, 2H), 1.54-148 (m, 2H), 1.17 (s,3H); ESI+MS: m/z: 364 ([M+H]⁺). The enantiomers of 98 were separatedusing chiral HPLC (method S) and afforded the pure enantiomers 98a and98b.

Example-99:5-(2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)ethoxy)benzo[d]thiazole

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpiperidine(0.045 g, 0.2 mmol) and 5-(2-bromoethoxy)benzo[d]thiazole (0.05 g, 0.2mmol, 1 equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC to afford 0.012 g of5-(2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)ethoxy)benzo[d]thiazole(Yield=14%). ¹H NMR (400 MHz, CD₃OD): δ 9.21 (s, 1H), 7.93 (d, J=9.2 Hz,1H), 7.58 (d, J=2.4 Hz, 1H), 7.16-7.13 (m, 1H), 7.06-7.03 (m, 4H),4.21-4.18 (m, 2H), 2.93-2.75 (m, 4H), 2.38-2.32 (m, 1H), 2.22 (d, J=12.0Hz, 1H), 2.08-2.00 (m, 1H), 1.90-1.87 (m, 1H), 1.63-1.46 (m, 2H), 1.57(s, 3H); ESI+MS: m/z 403 ([M+H]⁺). The enantiomers of 99 were separatedusing chiral HPLC (method D) and afforded the pure enantiomers 99a and99b.

Example-100:3-methyl-1-(2-phenoxyethyl)-3-(3-(trifluoromethyl)phenoxy)piperidine

tert-butyl3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

To a solution of tert-butyl 3-hydroxy-3-methylpiperidine-1-carboxylate(0.10 g, 0.46 mmol) in dry DMF (1 mL) under argon atmosphere was addedsodium hydride (60% suspension, 0.027 g, 0.69 mmol, 1.5 equiv) at 0° C.The reaction was warmed to room temperature and stirred for 10 min;3-(trifluoromethyl)-1-fluorobenzene (0.084 g, 0.511 mmol, 1.1 equiv) wasadded at 0° C.

The reaction mixture was heated at 100° C. in sealed tube for 16 h.After completion, the reaction was diluted with water and extracted withethyl acetate. The organic extract was dried over sodium sulfate,filtered and concentrated under reduced pressure. Purification usingsilica gel column chromatography (20% EtOAc/Hexanes as eluent) to afford0.065 g of tert-butyl3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate(Yield=39%).

3-Methyl-3-(3-(trifluoromethyl)phenoxy)piperidine

To a solution of tert-butyl3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (0.06 g,0.167 mmol) in diethyl ether (2 mL) under argon atmosphere was added 4.0M HCl in 1,4-dioxane (1 mL) at 0° C. The reaction mixture was stirred atroom temperature for 16 h. After completion, the solvent was removedunder reduced pressure to afford 0.047 g of3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine (Yield=95%).

3-Methyl-1-(2-phenoxyethyl)-3-(3-(trifluoromethyl)phenoxy)piperidine

Title compound was prepared from3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine (0.05 g, 0.17 mmol)and (2-bromoethoxy)benzene (0.037 g, 0.18 mmol, 1.1 equiv) using thegeneral methodology of Example-1. The crude was purified by preparativeHPLC to afford 0.01 g of3-methyl-1-(2-phenoxyethyl)-3-(3-(trifluoromethyl)phenoxy)piperidine(Yield=15%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.41-7.39 (m, 3H), 7.34 (s,1H), 7.29-7.24 (m, 2H), 6.94-6.88 (m, 3H), 4.01 (t, J=6.0 Hz, 2H),2.71-2.60 (m, 4H), 2.35-2.25 (m, 2H), 1.87-1.76 (m, 2H), 1.58-1.49 (m,2H), 1.23 (s, 3H); ESI+MS: m/z: 380 ([M+H]⁺).

Example-101:4-benzylidene-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-one

Title compound was prepared from piperidin-4-one hydrochloride (2 g,13.02 mmol) using general methodology of Example-1. Purification usingsilica gel chromatography (30% EtOAc/Hexanes as eluent) to afford 2 g of1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-one (Yield=53%).

Benzylidenetriphenyl-15-phosphane

To a solution of triphenylphosphine (10 g, 38.1 mmol) in toluene (150mL) was added benzyl bromide (7.1 g, 42 mmol, 1.1 equiv) at roomtemperature. The reaction mixture was stirred at 110° C. for 16 h. Aftercompletion, the obtained solid was filtered and washed with toluene toafford 10 g of benzylidenetriphenyl-15-phosphane (Yield=74%).

4-benzylidene-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

To a stirred solution of benzylidenetriphenyl-15-phosphane (9.8 g, 27.8mmol, 4 equiv) in THF (40 mL) was added n-BuLi (1.6 M in hexane, 6.55mL, 20.89 mmol 1.3 equiv) at 0° C. and stirred for 15 min. Then1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-one (2 g, 6.96 mmol,1 equiv) was added at 0° C. and warmed to room temperature for 4 h.After completion of the reaction, quenched with saturated NH₄Cl andextracted with EtOAc. The organic extract was separated, dried oversodium sulfate and concentrated under reduced pressure. Purificationusing silica gel chromatography (25% EtOAc/Hexanes as eluent) to afford1 g of 4-benzylidene-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=39%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.63-7.59 (m, 2H), 7.33-7.27(m, 3H), 7.21-7.18 (m, 3H), 7.08 (t, J=7.5 Hz, 1H), 6.28 (s, 1H), 4.22(t, J=6.0 Hz, 2H), 2.74 (t, J=5.0 Hz, 2H), 2.60 (t, J=5.0 Hz, 2H),2.52-2.50 (m, 2H), 2.41 (t, J=5.0 Hz, 2H), 2.31 (t, J=5.0 Hz, 2H);ESI+MS: m/z 362 ([M+H]⁺).

Example-102:1-Phenyl-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octane

To a stirred solution of4-benzylidene-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine (0.10mg, 0.27 mmol) in diethyl ether (5 mL) was added freshly prepareddiazomethane [prepared from NMU (0.28 g, 2.77 mmol, 10 equiv), 50%aqueous KOH (10 mL)] solution in diethyl ether (10 mL) and stirred at 0°C. for 1 h. Then Pd₂(dba)₃ (0.025 g, 0.02 mmol, 0.1 equiv) was added andthe reaction mixture was stirred at room temperature for 12 h. Aftercompletion, the reaction mass was filtered through celite bed and thefiltrate was concentrated under reduced pressure. The crude was purifiedby preparative HPLC to afford 30 mg of1-phenyl-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octane(Yield=29%). ¹H NMR (500 MHz, CD₃OD): δ 7.58-7.55 (m, 2H), 7.27-7.14 (m,6H), 7.07 (t, J=7.5 Hz, 1H), 4.25 (t, J=5.5 Hz, 2H), 2.88 (t, J=5.5 Hz,2H), 2.81-2.79 (m, 2H), 2.49-2.46 (m, 2H), 2.02-2.00 (m, 1H), 1.67-1.65(m, 2H), 1.29-1.27 (m, 2H), 0.99 (t, J=5.5 Hz, 1H), 0.84-0.82 (m, 1H);ESI+MS: m/z 376 ([M+H]⁺). The enantiomers of 102 were separated usingchiral HPLC (method T) and afforded the pure enantiomers 102a and 102b.

Example-103: 4-(Hydroxy(phenyl)methyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl) piperidin-4-ol

To a stirred solution of4-benzylidene-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine (0.5 g,1.38 mmol) in CH₂Cl₂ (5 mL) and water (1.5 mL) were addedN-Methylmorpholine N-oxide (0.19 g, 1.66 mmol, 1.2 equiv) followed bypotassium osmium(VI) oxide dihydrate (0.025 g, 0.06 mmol, 0.05 equiv) atroom temperature and stirred for 16 h. After completion, the reactionmass was poured into water and extracted with CH₂Cl₂. The organicextract layer was washed with saturated sodium thiosulphate solution,dried over sodium sulfate and concentrated under reduced pressure.Purification using silica gel chromatography (10% MeOH/CH₂Cl₂ as eluent)to afford 0.4 g of4-(hydroxy(phenyl)methyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(Yield=73%). ¹H NMR (500 MHz, CD₃OD): δ 7.58-7.55 (m, 2H), 7.41-7.40 (m,2H), 7.32 (t, J=7.5 Hz, 2H), 7.27-7.24 (m, 1H), 7.17 (d, J=8.5 Hz, 1H),7.07 (t, J=7.5 Hz, 1H), 4.42 (s, 1H), 4.26-4.24 (m, 2H), 3.71-3.69 (m,1H), 2.92-2.90 (m, 4H), 2.64-2.56 (m, 2H), 1.82-1.72 (m, 2H), 1.43-1.40(m, 1H); ESI+MS: m/z 396 ([M+H]⁺).

Example-104:4-(2-Chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

4-Methyl-4-(2-nitrophenoxy)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

Title compound was prepared from 4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl) piperidin-4-ol (0.50 g, 1.64 mmol) and 1-fluoro 2-nitrobenzene (0.23 g, 1.64 mmol, 1 equiv) using the general methodology ofstep 2 of key Intermediate-I at 80° C. for 16 h. Purification usingsilica gel chromatography (2% MeOH/CH₂Cl₂ as eluent) afforded 0.5 g of4-methyl-4-(2-nitrophenoxy)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=71%).

2-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)aniline

Title compound was prepared from4-methyl-4-(2-nitrophenoxy)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine (0.5 g, 1.17 mmol) using general methodology ofstep 3 of Key Intermediate-I. Purification using silica gelchromatography (2% MeOH/CH₂Cl₂ as eluent) to afford 0.3 g of2-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)aniline(Yield=64%).

4-(2-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

To a solution of2-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)aniline(0.20 g, 0.50 mmol) in HCl:H₂O (1:1, 1.5 mL) was added NaNO₂ in H₂O (0.5mL, 0.04 g, 0.65 mmol, 1.3 equiv) drop wise at 0° C. The reactionmixture was stirred at 0-5° C. for 1 h. Then a solution of CuCl (0.08 g,0.81 mmol, 1.6 equiv) in HCl: H₂O (0.5 mL) was added at 0° C. Thereaction was stirred at room temperature for 4 h. After completion, thereaction was quenched with NaOH_((aq)) and extracted with EtOAc. Theorganic extract was dried over sodium sulfate and concentrated underreduced pressure. The crude compound was purified by preparative HPLC toafford 0.02 g of4-(2-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=10%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.62-7.58 (m, 2H), 7.44 (d,J=8.0 Hz, 1H), 7.28-7.19 (m, 3H), 7.09-7.00 (m, 2H), 4.20 (t, J=5.6 Hz,2H), 2.74 (t, J=5.6 Hz, 2H), 2.66-2.53 (m, 4H), 2.02-1.96 (m, 2H),1.70-1.64 (m, 2H), 1.30 (s, 3H); ESI+MS: m/z 414 ([M+H]⁺).

Example-105:2-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)pyridine

To a solution of4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol (0.10 g,0.33 mmol) in toluene (1 mL) were added potassium tert-butoxide (0.11 g,0.98 mmol, 3 equiv) and 2-bromopyridine (0.05 g, 0.36 mmol, 1.1 equiv)at room temperature. The reaction was stirred at 120° C. in sealed tubefor 48 h. After completion, the reaction mass was concentrated underreduced pressure. The residue was diluted with water and extracted withEtOAc. The organic extract was separated, dried over sodium sulfate andconcentrated under reduced pressure. Purification using silica gelchromatography (2% MeOH/CH₂Cl₂ as eluent) to afford 0.05 g of(4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)pyridine(Yield=40%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.10 (d, J=3.2 Hz, 1H),7.64-7.59 (m, 3H), 7.27 (d, J=8.4 Hz, 1H), 7.10-7.06 (m, 1H), 6.92-6.90(m, 1H), 6.72 (d, J=8.0 Hz, 1H), 4.23-4.20 (m, 2H), 2.69-2.67 (m, 2H),2.67-2.66 (m, 2H), 2.44-2.42 (m, 2H), 2.31-2.25 (m, 2H), 1.76-1.72 (m,2H), 1.52 (s, 3H); ESI+MS: m/z 381 ([M+H]⁺).

Example-106:(4-Methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)(phenyl)methanone

tert-butyl 4-(methoxy(methyl)carbamoyl)-4-methylpiperidine-1-carboxylate

To a stirred solution of1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.20 g,0.82 mmol) in DMF (2 mL) was added N,O-dimethyl hydroxylamine. HCl (0.05g, 0.82 mmol, 1 equiv), EDCI (0.15 g, 0.82 mmol, 1 equiv) and HOBt (0.12g, 0.82 mmol, 1 equiv) followed by diisopropyl ethyl amine (0.1 g, 0.82mmol, 1 equiv) at 0° C. The reaction mixture was stirred at roomtemperature for 16 h. After completion, the reaction mass was quenchedwith water and extracted with ether. The organic extract was separated,dried over sodium sulfate and concentrated under reduced pressure.Purification using silica gel chromatography (3% MeOH/CH₂Cl₂ as eluent)to afford 0.20 g of tert-butyl4-(methoxy(methyl)carbamoyl)-4-methylpiperidine-1-carboxylate(Yield=85%).

tert-butyl 4-benzoyl-4-methylpiperidine-1-carboxylate

Title compound was prepared from tert-butyl4-(methoxy(methyl)carbamoyl)-4-methylpiperidine-1-carboxylate (0.20 g,0.69 mmol) using the general methodology of step 1 of Key Intermediate-Ifor 4 h. Purification using silica gel chromatography (2% MeOH/CH₂Cl₂ aseluent) to afford 0.08 g of tert-butyl4-benzoyl-4-methylpiperidine-1-carboxylate (Yield=37%).

1-(4-benzoyl-4-methyl-1λ⁴-piperidin-1-yl)-2,2,2-trifluoroethan-1-one

To a solution of tert-butyl 4-benzoyl-4-methylpiperidine-1-carboxylate(0.08 g, 0.26 mmol, and 1 equiv) in CH₂Cl₂ (2 mL) was addedtrifluoroacetic acid (1 mL) at 0-5° C. The reaction mixture was stirredat room temperature for 4 h. After completion, the volatiles wereevaporated under reduced pressure. The crude was washed with ether toafford 0.04 g of 1-(4-benzoyl-4-methyl-1λ⁴-piperidin-1-yl)-2, 2,2-trifluoroethan-1-one (Yield=51%).

(4-Methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)(phenyl)ethanone

Title compound was prepared from1-(4-benzoyl-4-methyl-114-piperidin-1-yl)-2, 2, 2-trifluoroethan-1-one(0.04 g, 0.13 mmol) using the general methodology of Example-1. Thecrude was purified using preparative HPLC to afford 0.012 g of1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-one (Yield=22%). ¹HNMR (400 MHz, CD₃OD): δ 7.69-7.67 (m, 2H) 7.56-7.41 (m, 5H), 7.15 (d,J=8.8 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 4.20 (t, J=5.6 Hz, 2H), 2.82-2.73(m, 4H), 2.40-2.29 (m, 4H), 1.72-1.65 (m, 2H), 1.43 (s, 3H); ESI+MS: m/z392 ([M+H]⁺).

Example-107:(4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)(phenyl)methanol

To a stirred solution of(4-Methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)(phenyl)ethanone (200 mg, 0.51 mmol) in MeOH (10 mL) was added NaBH₄ (39mg, 1.02 mmol) at 0° C. The reaction mixture was stirred at RT for 2hours. After completion of the reaction, volatiles were concentratedunder reduced pressure, water was added and the mixture was extractedwith EtOAc. The organic layer was separated, dried over Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyeluting with 2% MeOH in DCM to afford 0.18 g of(4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)(phenyl)methanol(Yield=90%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.62-7.58 (m, 2H), 7.30-7.18(m, 6H), 7.07 (t, J=7.6 Hz, 1H), 5.13 (d, J=4.0 Hz, 1H), 4.24 (d, J=4.0Hz, 1H), 4.17 (t, J=6.0 Hz, 2H), 2.72-2.67 (m, 4H), 2.26-2.15 (m, 2H),1.62-1.55 (m, 2H), 1.39-1.33 (m, 1H), 0.91 (d, J=12.8 Hz, 1H), 0.76 (s,3H); ESI+MS: m/z 394 ([M+H]⁺). The enantiomers of 107 were separatedusing chiral HPLC (method B) and afforded the pure enantiomers 107a and107b.

Example-108:3-(4-Chlorophenoxy)-3-methyl-1-(2-methyl-1-phenoxypropan-2-yl)piperidine

Methyl 2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)-2-methylpropanoate

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpiperidine(0.40 g, 1.77 mmol) using the general methodology of Example-1.Purification using silica gel chromatography (30% EtOAc/Hexanes aseluent) afforded 0.28 g of Methyl2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)-2-methylpropanoate(Yield=48%).

2-(3-(4-Chlorophenoxy)-3-methylpiperidin-1-yl)-2-methylpropan-1-ol

To a solution of Methyl2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)-2-methylpropanoate (0.12g, 0.36 mmol) in ethanol (1 mL) and THF (2 mL) was added LiBH₄ (0.024 g,1.1 mmol, 3 equiv) at 0° C. The reaction mixture was stirred at roomtemperature for 16 h. After completion, the reaction was quenched withcold water and extracted with EtOAc. The organic layer was separated,dried over sodium sulfate and concentrated under pressure. Purificationusing silica gel chromatography (2% MeOH/CH₂Cl₂ as eluent) to afford0.06 g of2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)-2-methylpropan-1-ol(Yield=54%).

2-(3-(4-Chlorophenoxy)-3-methylpiperidin-1-yl)-2-methylpropylmethanesulfonate

To a stirred solution of2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)-2-methylpropan-1-ol (0.10g, 0.33 mmol) in CH₂Cl₂ (4 mL) were added triethyl amine (0.05 g, 0.50mmol, 1.5 equiv) and mesyl chloride (0.04 g, 0.40 mmol, 1.2 equiv) at 0°C. The reaction mixture was stirred at room temperature for 16 h. Aftercompletion, diluted with water and extracted with CH₂Cl₂. The organicextract was separated, dried over sodium sulfate and concentrated underreduced pressure to afford 0.095 g of2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)-2-methylpropylmethanesulfonate (Yield=75%).

3-(4-chlorophenoxy)-3-methyl-1-(2-methyl-1-phenoxypropan-2-yl)piperidine

Title compound was prepared from2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)-2-methylpropylmethanesulfonate (0.09 g, 0.24 mmol) and phenol (0.04 g, 0.48 mmol, 2equiv) using the general methodology of Example-1. The crude waspurified using preparative HPLC to afford 0.015 g of3-(4-chlorophenoxy)-3-methyl-1-(2-methyl-1-phenoxypropan-2-yl)piperidine(Yield=16%). ¹H NMR (400 MHz, CD₃OD): δ 7.26-7.18 (m, 4H), 7.06-6.94 (m,5H), 2.69-2.65 (m, 3H), 2.56-2.52 (m, 3H), 1.83-1.75 (m, 1H), 1.73-1.57(m, 3H), 1.31 (s, 3H), 1.24 (s, 6H); ESI+MS: m/z 374 ([M+H]⁺).

Example-109: 2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)benzonitrile

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.10 g, 0.44 mmol) and 2-(2-bromoethoxy)benzonitrile(0.12 g, 0.52 mmol, 1.2 equiv) using the general methodology ofExample-1. Purification using silica gel chromatography (2% MeOH/CH₂Cl₂as eluent) to afford 0.12 g of2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)benzonitrile (Yield=80%).¹H NMR (500 MHz, CD₃OD): δ 7.65 (t, J=8.5 Hz, 2H), 7.29-7.20 (m, 3H),7.11-7.01 (m, 4H), 4.33 (t, J=5.5 Hz, 2H), 2.98 (t, J=5.5 Hz, 2H),2.87-2.85 (m, 4H), 2.05-2.03 (m, 2H), 1.79-1.73 (m, 2H), 1.29 (s, 3H);ESI+MS: m/z 337 ([M+H]⁺).

Example-10: 4-methyl-4-phenoxy-1-(2-(2-(trifluoromethoxy) phenoxy)ethyl)piperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidine (0.10 g,0.52 mmol) and 1-(2-bromoethoxy)-2-(trifluoromethoxy)benzene (0.14 g,0.52 mmol, 1 equiv) using the general methodology of Example-1. Thecrude was purified using silica gel chromatography (2% MeOH/CH₂Cl₂ aseluent) to afford 0.12 g of the4-methyl-4-phenoxy-1-(2-(2-(trifluoromethoxy) phenoxy)ethyl)piperidine(Yield=56%). ¹H NMR (500 MHz, CD₃OD): δ 7.34-7.18 (m, 5H), 7.08-7.00 (m,4H), 4.26 (t, J=5.5 Hz, 2H), 2.95 (t, J=5.5 Hz, 2H), 2.84-2.83 (m, 4H),2.05-2.02 (m, 2H), 1.78-1.73 (m, 2H), 1.03 (s, 3H); ESI+MS: m/z 396([M+H]⁺).

Example-111:N,N-dimethyl-2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)aniline

2-(Allyloxy)-N,N-dimethylaniline

To a solution of 2-(dimethylamino)phenol (0.5 g, 3.64 mmol) in acetone(10 mL) was added potassium carbonate (1.5 g, 10.9 mmol, 3 equiv) atroom temperature. Then allyl bromide (0.66 g, 5.4 mmol, 1.5 equiv) wasadded and maintained the reaction at 80° C. for 16 h. After completion,the reaction mass was filtered and the filtrate was concentrated underreduced pressure. Then water was added to the residue and extracted withEtOAc. The organic extract was separated, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. Purification using silica gelchromatography (15% EtOAc/Hexanes as eluent) to afford 0.9 g of2-(allyloxy)-N,N-dimethylaniline (Quantitative)

2-(2-(Dimethylamino)phenoxy)acetaldehyde

To a stirred solution of 2-(allyloxy)-N,N-dimethylaniline (0.20 g, 1.12mmol) in mixture of acetone:H₂O (3:2.5 mL) was added potassiumosmium(VI) oxide dihydrate (0.015 g, 0.03 mmol, 0.03 equiv) at 0° C. andstirred for 10 min. Then sodium periodate (0.96 g, 4.5 mmol, 4 equiv)was added portion wise to the reaction mixture and stirred at roomtemperature for 3 h. After completion, the reaction was filtered; thefiltrate was concentrated under reduced pressure. The residue wasdiluted with water and extracted with EtOAc. The organic extract wasseparated, dried over sodium sulfate and concentrated under reducedpressure. Purification using silica gel chromatography (2% MeOH/CH₂Cl₂as eluent) to afford 0.08 g of 2-(2-(dimethylamino)phenoxy)acetaldehyde(Yield=39%).

N,N-dimethyl-2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)aniline

To a stirred solution of 4-methyl-4-phenoxypiperidine (0.10 g, 0.52mmol) in CH₂Cl₂ (3 mL) were added sodium triacetoxyborohydride (0.33 g,1.56 mmol, 3 equiv), 2-(2-(dimethylamino)phenoxy)acetaldehyde (0.09 g,0.52 mmol, 1 equiv) and acetic acid (1 mL) at 0° C. The reaction mixturewas stirred at room temperature for 16 h. After completion, the reactionmass was diluted with water and extracted with CH₂Cl₂. The organicextract was separated, dried over sodium sulfate and concentrated underreduced pressure. Purification using silica gel chromatography (2%MeOH/CH₂Cl₂ as eluent) to afford 0.08 g of N,N-dimethyl-2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)aniline(Yield=4%). ¹H NMR (400 MHz, CD₃OD): δ 7.28-7.24 (m, 2H), 7.06-6.90 (m,7H), 4.19 (t, J=6.0 Hz, 2H), 2.95 (t, J=6.0 Hz, 2H), 2.80-2.78 (m, 4H),2.74 (s, 6H), 2.05-2.00 (m, 2H), 1.77-1.70 (m, 2H), 1.28 (s, 3H);ESI+MS: m/z 355 ([M+H]⁺).

Example-112:N,4-Dimethyl-N-phenyl-1-(2-(2-(trifluoromethylphenoxy)ethyl)piperidin-4-amine

tert-butyl 4-methyl-4-((4-nitrophenyl)amino)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-amino-4-methylpiperidine-1-carboxylate (0.50 g, 2.33 mmol) in DMF (10mL) was added K₂CO₃ (967 mg, 7.0 mmol) at RT. After 10 minutes,1-fluoro-4-nitrobenzene (395 mg, 2.8 mmol) was added at RT and themixture was stirred at 110° C. for 48 h. The reaction was quenched withwater and extracted with EtOAc. The organic layer was separated, driedover Na₂SO₄, filtered and concentrated. The crude compound was purifiedby column chromatography eluting with 20% EtOAc in hexane to afford 0.20g of tert-butyl4-methyl-4-((4-nitrophenyl)amino)piperidine-1-carboxylate (Yield=25%).

tert-butyl4-methyl-4-(methyl(4-nitrophenyl)amino)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-methyl-4-((4-nitrophenyl)amino)piperidine-1-carboxylate (0.25 g, 0.74mmol) in DMF (2 mL) was added sodium hydride (60% suspension, 0.065 g,2.71 mmol, 2 equiv) at 0° C. and stirred for 15 min. Then methyl iodide(0.10 g, 0.74 mmol, 1 equiv) was added at 0° C. and the reaction mixturewas stirred at 0° C. for 1 h. After completion, the reaction was dilutedwith water and extracted with EtOAc. The organic extract was dried oversodium sulfate and concentrated under reduced pressure to afford (0.20g) tert-butyl4-methyl-4-(methyl(4-nitrophenyl)amino)piperidine-1-carboxylate(Yield=77%).

tert-butyl4-((4-aminophenyl)(methyl)amino)-4-methylpiperidine-1-carboxylate

Title compound was prepared from tert-butyl4-methyl-4-(methyl(4-nitrophenyl)amino) piperidine-1-carboxylate (0.25g, 0.71 mmol) using general methodology of step 3 of Key-Intermediate-Ito afford 0.20 g of tert-butyl 4-((4-aminophenyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (Yield=88%).

tert-butyl 4-methyl-4-(methyl(phenyl)amino)piperidine-1-carboxylate

Title compound was prepared from tert-butyl4-((4-aminophenyl)(methyl)amino)-4-methylpiperidine-1-carboxylate (0.20g, 0.62 mmol) using the general methodology of step 1 of keyIntermediate-VI at 80° C. for 1 h. Purification using silica gelchromatography (20% EtOAc/Hexanes as eluent) to afford 0.09 g oftert-butyl 4-methyl-4-(methyl(phenyl)amino)piperidine-1-carboxylate(Yield=47%).

N,4-Dimethyl-N-phenylpiperidin-4-amine hydrochloride

Title compound was prepared from tert-butyl4-methyl-4-(methyl(phenyl)amino)piperidine-1-carboxylate (0.09 g, 0.29mmol) using general methodology of step 2 of key Intermediate-VI. Thecrude was triturated with diethyl ether to afford 0.06 g ofN,4-dimethyl-N-phenylpiperidin-4-amine hydrochloride (Yield=84%).

N,4-Dimethyl-N-phenyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-amine

Title compound was prepared from N,4-dimethyl-N-phenylpiperidin-4-aminehydrochloride (0.06 g, 0.25 mmol) using general methodology ofExample-1. Purification using silica gel chromatography (10% MeOH/CH₂Cl₂as eluent) to afford 0.04 g of theN,4-dimethyl-N-phenyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-amine(Yield=41%). ¹H NMR (400 MHz, CD₃OD): δ 7.62-7.58 (m, 2H), 7.30-7.26 (m,2H), 7.23-7.20 (m, 3H), 7.15-7.11 (m, 2H), 4.38 (t, J=5.2 Hz, 2H),3.31-3.30 (m, 4H), 2.97-2.95 (m, 2H), 2.73 (s, 3H), 2.05-2.02 (m, 2H),1.68-1.61 (m, 2H), 1.17 (s, 3H); ESI+MS: m/z 393 ([M+H]⁺).

Example-113:1-phenyl-7-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,7-diazaspiro[3.5]nonane

tert-butyl 1-phenyl-1,7-diazaspiro[3.5]nonane-7-carboxylate

To a solution of tert-butyl-1,7-diazaspiro[3.5]nonane-7-carboxylatehydrochloride (0.30 g, 1.14 mmol) in toluene (2 mL) were added sodiumtertiary butoxide (0.33 g, 3.40 mmol, 3 equiv), Pd(OAc)₂ (0.025 g, 0.11mmol, 0.1 equiv) followed by (+/−) BINAP (0.035 g, 0.05 mmol, 0.05equiv) at room temperature and degassed for 15 min with argon. Thereaction mixture was maintained at 110° C. for 16 h in sealed tube.After completion, the reaction was diluted with water and extracted withEtOAc. The organic extract was separated, dried over sodium sulfate andconcentrated under reduced pressure. Purification using silica gelchromatography (10% EtOAc in Hexane as eluent) to afford 0.15 g oftert-butyl 1-phenyl-1,7-diazaspiro[3.5]nonane-7-carboxylate (Yield=43%).

1-Phenyl-1,7-diazaspiro[3.5]nonane hydrochloride

Title compound was prepared from tert-butyl1-phenyl-1,7-diazaspiro[3.5]nonane-7-carboxylate (0.17 g, 0.56 mmol, 1equiv) using general methodology of step 2 of Key Intermediate-VI toafford 0.1 g of 1-phenyl-1,7-diazaspiro[3.5]nonane hydrochloride(Yield=74%).

1-phenyl-7-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,7-diazaspiro[3.5]nonane

Title compound was prepared from 1-phenyl-1,7-diazaspiro[3.5]nonanehydrochloride (0.10 g, 0.42 mmol) using the general methodology ofExample-1. The crude was purified using preparative HPLC to afford 0.012g of the1-phenyl-7-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,7-diazaspiro[3.5]nonane(Yield=7%). ¹H NMR (400 MHz, CD₃OD): δ 7.58-7.54 (m, 2H), 7.19-7.11 (m,3H), 7.05 (t, J=7.6 Hz, 1H), 6.67 (t, J=7.6 Hz, 1H), 6.57-6.66 (m, 2H),4.25 (t, J=5.6 Hz, 2H), 3.69-3.65 (m, 2H), 3.06-3.03 (m, 2H), 2.87 (t,J=5.6 Hz, 2H), 2.36-2.25 (m, 4H), 2.14 (t, J=7.2 Hz, 2H), 1.74-1.71 (m,2H); ESI+MS: m/z 391 ([M+H]⁺).

Example-114:4-benzyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol

tert-butyl 4-benzyl-4-hydroxypiperidine-1-carboxylate

Title compound was prepared from tert-butyl4-oxopiperidine-1-carboxylate (3 g, 15.06 mmol) and (bromomethyl)benzene(5.15 g, 30.1 mmol, 2 equiv) using general methodology of step 1 of keyIntermediate-I for 4 h. Purification using silica gel chromatography(20% EtOAc/Hexanes as eluent) to afford 2 g of tert-butyl4-benzyl-4-hydroxypiperidine-1-carboxylate (Yield=45%).

4-benzylpiperidin-4-ol hydrochloride

Title compound was prepared from tert-butyl4-benzyl-4-hydroxypiperidine-1-carboxylate (1 g, 3.43 mmol) usinggeneral methodology of step 2 of key intermediate-VI to afford 0.75 g of4-benzylpiperidin-4-ol hydrochloride (Yield=96%).

4-benzyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol

Title compound was prepared from 4-benzylpiperidin-4-ol hydrochloride(0.75 g, 3.29 mmol) using the general methodology of Example-1.Purification using silica gel chromatography (5% MeOH/CH₂Cl₂ as eluent)to afford 0.8 g of the4-benzyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(Yield=64%). ¹H NMR (400 MHz, CD₃OD): δ 7.57-7.53 (m, 2H), 7.28-7.15 (m,6H), 7.05 (t, J=7.6 Hz, 1H), 4.23 (t, J=5.6 Hz, 2H), 2.89 (t, J=5.6 Hz,2H), 2.84-2.81 (m, 2H), 2.76 (s, 2H), 2.65-2.59 (m, 2H), 1.76-1.68 (m,2H), 1.56-1.53 (m, 2H); ESI+MS: m/z 380 ([M+H]⁺).

Example-115:4-benzyl-4-fluoro-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

To a stirred solution of4-benzyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol (0.2 g,0.52 mmol) in CH₂Cl₂ (5 mL) was added DAST (0.10 g, 0.63 mmol, 1.2equiv) at −78° C. The reaction mixture was stirred at 0° C. for 1 h.After completion, the reaction mass was quenched with saturated NaHCO₃solution and extracted with CH₂Cl₂. The organic extract was dried oversodium sulfate and concentrated under reduced pressure. Purificationusing silica gel chromatography (4% MeOH/CH₂Cl₂ as eluent) to afford0.05 g of 4-benzyl-4-fluoro-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)(Yield=25%). ¹H NMR (400 MHz, CD₃OD): δ 7.57-7.53 (m, 2H), 7.29-7.15 (m,6H), 7.04 (t, J=7.6 Hz, 1H), 4.23 (t, J=5.6 Hz, 2H), 2.94 (s, 1H),2.88-2.85 (m, 5H), 2.51-2.45 (m, 2H), 1.83-1.69 (m, 4H); ESI+MS: m/z 382([M+H]⁺).

Example-116:3-(4-Methyl-4-phenoxypiperidin-1-yl)-1-(2-(trifluoromethyl)phenyl)propan-1-one

N-Methoxy-N-methyl-2-(trifluoromethyl)benzamide

To a stirred solution of 2-(trifluoromethyl)benzoic acid (3 g, 15.78mmol) and N,O-dimethylhydroxylamine hydrochloride (1.84 g, 18.94 mmol,1.2 equiv) in DMF (20 mL) was added HATU (9.0 g, 23.7 mmol) and DIPEA(5.47 mL, 31.6 mmol). The reaction mixture was stirred at RT for 16 h.After completion of the reaction (monitored by TLC), the mixture wasdiluted with water and extracted with ethyl acetate. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated. Purification usingsilica gel column chromatography (50% EtOAc/Hexanes as eluent) afforded3 g of N-methoxy-N-methyl-2-(trifluoromethyl)benzamide (Yield=82%).

1-(2-(trifluoromethyl)phenyl)prop-2-en-1-one

To a solution N-methoxy-N-methyl-2-(trifluoromethyl)benzamide (1 g, 4.29mmol) in THF (10 mL) was added vinyl magnesium bromide (5.2 mL, 5.15mmol, 1.2 equiv) under argon atmosphere at 0° C.; the reaction mixturewas stirred at room temperature for 12 h, quenched with saturatedammonium chloride and extracted with ethyl acetate. The organic extractwas dried over sodium sulfate and concentrated under reduced pressure.Purification using silica gel column chromatography (20% EtOAc/Hexanesas eluent) to afford 0.2 g of1-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (Yield=23%).

3-(4-methyl-4-phenoxypiperidin-1-yl)-1-(2-(trifluoromethyl)phenyl)propan-1-one

To a solution of 4-methyl-4-phenoxypiperidine hydrochloride (0.1 g, 0.43mmol) and 1-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (0.088 g, 0.43mmol, 1 equiv) in acetone (0.5 mL) under argon atmosphere was addedtriethylamine (0.18 mL, 1.30 mmol, 3 equiv) at room temperature. Thereaction mixture was heated at 80° C. in sealed tube for 16 h. Aftercompletion, the reaction was diluted with water and extracted with ethylacetate. The organic extract was dried over sodium sulfate, filtered andconcentrated under reduced pressure. Purification using silica gelcolumn chromatography to afford 0.05 g of3-(4-methyl-4-phenoxypiperidin-1-yl)-1-(2-(trifluoromethyl)phenyl)propan-1-one(Yield=29%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.83-7.68 (m, 4H), 7.27 (t,J=7.6 Hz, 2H), 7.06-6.96 (m, 3H), 3.09-3.07 (m, 2H), 2.67-2.66 (m, 2H),2.46-2.44 (m, 4H), 1.84-1.82 (m, 2H), 1.59-1.53 (m, 2H), 1.22 (s, 3H);ESI+MS: m/z 392 ([M+H]⁺).

Example-117:4-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-2-(2-(trifluoromethyl)phenyl)butan-2-ol

Title compound was prepared from3-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-1-(2-(trifluoromethyl)phenyl)propan-1-one(0.05 g, 0.12 mmol) using the general methodology of step 1 keyintermediate-I. Purification by column chromatography (2% MeOH/CH₂Cl₂ aseluent) to afford 0.02 g of4-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-2-(2-(trifluoromethyl)phenyl)butan-2-ol(Yield=39%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.75-7.73 (m, 1H), 7.65-7.63(m, 1H), 7.60-7.56 (m, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.31-7.27 (m, 2H),7.00-6.96 (m, 2H), 6.48 (s, 1H), 2.58-2.55 (m, 1H), 2.43-2.36 (m, 2H),2.34-2.30 (m, 3H), 2.28-2.11 (m, 1H), 1.97-1.90 (m, 1H), 1.80-1.78 (m,2H), 1.57-1.51 (m, 2H), 1.48 (s, 3H), 1.20 (s, 3H); ESI+MS: m/z 442([M+H]⁺).

Example-118:4-Methyl-4-phenoxy-1-(3-(2-(trifluoromethyl)phenyl)propyl)piperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.1 g, 0.43 mmol) and1-(3-bromopropyl)-2-(trifluoromethyl)benzene (0.11 g, 0.43 mmol, 1equiv) using the general methodology of Example-1. Purification bycolumn chromatography (2% MeOH/CH₂Cl₂ as eluent) to afford 0.11 g of4-methyl-4-phenoxy-1-(3-(2-(trifluoromethyl)phenyl)propyl)piperidine(Yield=65%). ¹H NMR (400 MHz, CD₃OD): δ 7.63 (d, J=8.0 Hz, 1H), 7.54 (t,J=7.6 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.29-7.23(m, 2H), 7.07-7.03 (m, 1H), 6.98 (d, J=8.0 Hz, 2H), 2.84-2.81 (m, 6H),2.70-2.67 (m, 2H), 2.07-2.04 (m, 2H), 1.96-1.88 (m, 2H), 1.78-1.71 (m,2H), 1.27 (s, 3H); ESI+MS: m/z 378 ([M+H]⁺).

Example-119:4-methyl-4-phenoxy-1-(3-(2-(trifluoromethyl)phenyl)propyl)piperidine

To a stirred solution of4-(hydroxy(phenyl)methyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol (0.04 g, 0.1 mmol) in acetone (5 mL) underargon atmosphere were added 2,2-dimethoxy propane (0.105 g 1.01 mmol, 10equiv) and 10-camphorsulfonic acid (0.011 g, 0.051 mmol, 0.5 equiv) atroom temperature and the reaction was stirred for 5 h. After completion,the reaction was quenched with saturated NaHCO₃ and extracted withCH₂Cl₂. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. Purification using silica gelcolumn chromatography (2% MeOH/CH₂Cl₂ as eluent) afforded 0.015 g of4-methyl-4-phenoxy-1-(3-(2-(trifluoromethyl)phenyl) propyl)piperidine(Yield=34%). ¹H NMR (400 MHz, CD₃OD): δ 7.55-7.51 (m, 2H), 7.39-7.30 (m,5H), 7.12 (d, J=8.4 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 4.87 (s, 1H), 4.17(t, J=5.6 Hz, 2H), 2.83-2.80 (m, 1H), 2.75-2.72 (m, 2H), 2.63-2.56 (m,1H), 2.53-2.52 (m, 1H), 2.49-2.46 (m, 1H) 1.94-1.93 (m, 1H), 1.79-1.77(m, 1H), 1.56 (s, 3H), 1.47 (s, 3H), 1.47-1.46 (m, 1H), 0.90-0.79 (m,1H); ESI+MS: m/z 436 ([M+H]⁺).

Example-120: 4-(4-chlorophenoxy)-4-methyl-1-(4-phenoxybutyl)piperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.1 g, 0.44 mmol) and (4-bromobutoxy)benzene (0.122 g, 0.53 mmol, 1.2equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC purification to afford 0.018 g of4-(4-chlorophenoxy)-4-methyl-1-(4-phenoxybutyl)piperidine (Yield=11%).¹H NMR (400 MHz, CD₃OD): δ 7.26-7.22 (m, 4H), 6.99-6.97 (m, 2H),6.91-6.87 (m, 3H), 4.00 (t, J=6.0 Hz, 2H), 2.65-2.57 (m, 4H), 2.52-2.48(m, 2H), 2.02-1.97 (m, 2H), 1.81-1.68 (m, 6H), 1.27 (s, 3H); ESI+MS: m/z374 ([M+H]⁺).

Example-121: 4-Methyl-4-phenoxy-1-(4-phenoxybutyl)piperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.09 g, 0.4 mmol) and (4-bromobutoxy)benzene (0.11 g, 0.47 mmol, 1.2equiv) using the general methodology of Example-1. The crude waspurified by preparative HPLC purification to afford 0.008 g of4-methyl-4-phenoxy-1-(4-phenoxybutyl)piperidine (Yield=6%). ¹H NMR (400MHz, CD₃OD): δ 7.28-7.22 (m, 4H), 7.06-6.98 (m, 3H), 6.90-6.87 (m, 3H),4.00 (t, J=6.0 Hz, 2H), 2.64-2.63 (m, 4H), 2.51-2.47 (m, 2H), 2.03-1.98(m, 2H), 1.81-1.67 (m, 6H), 1.27 (s, 3H); ESI+MS: m/z 340 ([M+H]⁺).

Example-122:4-(4-Chlorophenoxy)-1-(2-(5-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.12 g, 0.53 mmol) and2-(2-bromoethoxy)-4-fluoro-1-(trifluoromethyl)benzene using the generalmethodology of Example-1. Purification by column chromatography (2%MeOH/CH₂Cl₂ as eluent) to afford 0.01 g of4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine(Yield=4%). ¹H NMR (400 MHz, CD₃OD): δ 7.63-7.60 (m, 1H), 7.27-7.23 (m,2H), 7.04-6.96 (m, 3H), 6.83-6.78 (m, 1H), 4.26 (t, J=5.6 Hz, 2H), 2.93(t, J=5.2 Hz, 2H), 2.79-2.76 (m, 4H), 2.03-1.97 (m, 2H), 1.76-1.69 (m,2H), 1.28 (s, 3H); ESI+MS: m/z 432 ([M+H]⁺).

Example-123: 4-methoxy-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

tert-butyl 4-methoxy-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(0.15 g, 0.69 mmol) in DMF (0.5 mL) under argon atmosphere were addedsodium hydride (60%, suspension, 0.11 g, 4.67 mmol, 4 equiv) andiodomethane (0.198 mL, 1.3 mmol, 2 equiv) at 0° C. The reaction mixturewas stirred at room temperature for 12 h. After completion, the reactionwas quenched with ice cold water and extracted with EtOAc. The combinedorganic extract was dried sodium sulfate and concentrated under reducedpressure. Purification using silica gel column chromatography (10%EtOAc/Hexanes as eluent) to afford 0.1 g of tert-butyl4-methoxy-4-methylpiperidine-1-carboxylate (Yield=63%).

2,2,2-trifluoro-1-(4-methoxy-4-methyl-1λ⁴-piperidin-1-yl)ethan-1-one

To a solution of tert-butyl 4-methoxy-4-methylpiperidine-1-carboxylate(0.1 g, 0.43 mmol) in CH₂Cl₂ was added trifluoroacetic acid (0.16 mL,2.18 mmol, 5 equiv) at 0-5° C. The reaction was stirred at roomtemperature for 4 h. After completion, the volatiles were removed underreduced pressure to afford 0.1 g of2,2,2-trifluoro-1-(4-methoxy-4-methyl-1λ⁴-piperidin-1-yl)ethan-1-one(Quantitative).

4-methoxy-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl) piperidine

Title compound was prepared from 4-methoxy-4-methylpiperidine (0.1 g,0.4 mmol) using the general methodology of Example-1. Purification usingcolumn chromatography (2% MeOH/CH₂Cl₂ as eluent) to afford 0.1 g of4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine(Yield=69%). ¹H NMR (400 MHz, CD₃OD): δ 7.59-7.55 (m, 2H), 7.19 (d,J=8.8 Hz, 1H), 7.08 (t, J=8.0 Hz, 1H), 4.30 (t, J=5.6 Hz, 2H), 3.19 (s,3H), 3.06-3.03 (m, 2H), 2.90-2.87 (m, 2H), 2.76-2.70 (m, 2H), 1.85 (d,J=13.2 Hz, 2H), 1.67-1.60 (m, 2H), 1.18 (s, 3H); ESI+MS: m/z 318([M+H]⁺).

Example-124:4-Methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol

Title compound was prepared from 4-methylpiperidin-4-ol hydrochloride (3g, 19.7 mmol) using the general methodology of Example-1. Purificationusing column chromatography (2% MeOH/CH₂Cl₂ as eluent) to afford 4 g of4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(Yield=67%). ¹H NMR (400 MHz, CD₃OD): δ 7.58-7.55 (m, 2H), 7.18 (d,J=8.8 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 4.28 (t, J=5.2 Hz, 2H), 2.99-2.97(m, 2H), 2.83-2.72 (m, 4H), 1.72-1.63 (m, 4H), 1.22 (s, 3H); ESI+MS: m/z304 ([M+H]⁺).

Example-125:4-(4-Chlorophenoxy)-4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.15 g, 0.66 mmol) using the general methodology of Example-1. Thecrude was purified by preparative HPLC to afford 0.05 g of4-(4-chlorophenoxy)-4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine (Yield=18%). ¹H NMR (400 MHz, CD₃OD): δ 7.58 (d, J=8.8 Hz,2H), 7.27-7.23 (m, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.00-6.96 (m, 2H), 4.22(t, J=11.2 Hz, 2H), 2.90 (t, J=5.6 Hz, 2H), 2.75-2.70 (m, 4H), 2.03-2.00(m, 2H), 1.78-1.71 (m, 2H), 1.29 (s, 3H); ESI+MS: m/z 414 [M+H]⁺).

Example-126: 4-(Benzyloxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl) piperidine

tert-butyl 4-(benzyloxy)-4-methylpiperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate(0.3 g, 1.39 mmol) in THF (5 mL) were added sodium hydride (60%suspension, 0.22 g 9.29 mmol, 4 equiv) under argon atmosphere and benzylbromide (0.477 g, 2.79 mmol, 2 equiv) at 0° C. The reaction mixture wasstirred at room temperature for 12 h. After completion, the reaction wasquenched with cold water and extracted with EtOAc. The organic extractwas dried over sodium sulfate, filtered and concentrated under reducedpressure. Purification using silica gel column chromatography (10%EtOAc/Hexanes as eluent) to afford 0.12 g of tert-butyl4-(benzyloxy)-4-methylpiperidine-1-carboxylate (Yield=28%).

1-(4-(benzyloxy)-4-methyl-1λ⁴-piperidin-1-yl)-2,2,2-trifluoroethan-1-one

Title compound was prepared from tert-butyl4-(benzyloxy)-4-methylpiperidine-1-carboxylate (0.12 g, 0.39 mmol) usingthe general methodology of Example 123 to afford 0.1 g of1-(4-(benzyloxy)-4-methyl-1λ⁴-piperidin-1-yl)-2,2,2-trifluoroethan-1-one(Quantitative). ESI+MS: m/z 206 ([M+H]⁺).

4-(benzyloxy)-4-methyl-1-(2-(2-(trifluoromethyl) phenoxy)ethyl)piperidine

Title compound was prepared from 4-(benzyloxy)-4-methylpiperidine as TFAsalt (0.1 g, 0.33 mmol) using the general methodology of Example-1. Thecrude was purified using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) to afford 0.07 g of4-(benzyloxy)-4-methyl-1-(2-(2-(trifluoromethyl) phenoxy)ethyl)piperidine (Yield=54%). ¹H NMR (400 MHz, CD₃OD): δ 7.59-7.56 (m, 2H),7.35-7.33 (m, 2H), 7.29 (t, J=6.8 Hz, 2H), 7.24-7.18 (m, 2H), 7.08 (t,J=7.6 Hz, 1H), 4.44 (s, 2H), 4.30 (t, J=5.2 Hz, 2H), 3.07-3.04 (m, 2H),2.92-2.79 (m, 4H), 1.99-1.96 (m, 2H), 1.72 (dt, J=11.6, 4.4 Hz, 2H),1.30 (s, 3H); ESI+MS: m/z 394 ([M+H]⁺).

Example-127:6-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)benzo[d]oxazole

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.08 g, 0.354 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (4% MeOH/CH₂Cl₂ aseluent) and preparative HPLC to afford 0.006 g of6-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)benzo[d]oxazole(Yield=4%). ¹H NMR (400 MHz, CD₃OD): δ 8.35 (s, 1H), 7.62 (d, J=8.8 Hz,1H), 7.30 (d, J=2.4 Hz, 1H), 7.25 (dd, J=6.8, 2.4 Hz, 2H), 7.07 (dd,J=6.8, 2.4 Hz, 1H), 6.99 (dd, J=6.8, 2.0 Hz, 2H), 4.26 (t, J=5.6 Hz,2H), 3.05-3.03 (m, 2H), 2.91-2.89 (m, 4H), 2.06 (d, J=13.2 Hz, 2H),1.83-1.76 (m, 2H), 1.29 (s, 3H); ESI+MS: m/z 387 ([M+H]⁺).

Example-128:3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-4-(trifluoromethyl)pyridine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.09 g, 0.399 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (4% MeOH/CH₂Cl₂ aseluent) and preparative HPLC to afford 0.015 g of3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-4-(trifluoromethyl)pyridine(Yield=9%). ¹H NMR (400 MHz, CD₃OD): δ 8.60 (s, 1H), 8.36 (d, J=5.2 Hz,1H), 7.61 (d, J=4.8 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz,2H), 4.42 (t, J=5.6 Hz, 2H), 2.94 (t, J=5.6 Hz, 2H), 2.77-2.74 (m, 4H),2.01-1.97 (m, 2H), 1.75-1.68 (m, 2H), 1.28 (s, 3H); ESI+MS: m/z 415([M+H]⁺).

Example-129:2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-N-(2-(trifluoromethyl)phenyl)acetamide

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidine(0.2 g, 0.886 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (15% EtOAc/Hexanesas eluent) afforded 0.04 g of2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-N-(2-(trifluoromethyl)phenyl)acetamide(Yield=11%). ¹H NMR (400 MHz, CD₃OD): δ 8.23 (d, J=8.4 Hz, 1H), 7.69 (d,J=8.0 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.26-7.23(m, 2H), 7.01-6.98 (m, 2H), 3.21 (s, 2H), 2.84-2.78 (m, 2H), 2.72-2.67(m, 2H), 2.04 (d, J=14.0 Hz, 2H), 1.82-1.74 (m, 2H), 1.30 (s, 3H);ESI+MS: m/z 427 ([M+H]⁺).

Example-130: 4-Methyl-1-(2-phenoxyethyl)piperidin-4-ol

Title compound was prepared from 4-methylpiperidin-4-ol hydrochloride(0.1 g, 0.65 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (3% MeOH/CH₂Cl₂ aseluent) to afford 0.1 g of1-(2-(2-fluorophenoxy)ethyl)-4-methyl-N-phenylpiperidine-4-carboxamide(Yield=64%). ¹H NMR (400 MHz, CD₃OD): δ 7.29-7.25 (m, 2H), 6.95-6.91 (m,3H), 4.17 (t, J=5.2 Hz, 2H), 2.96 (t, J=5.6 Hz, 2H), 2.84-2.81 (m, 2H),2.76-2.70 (m, 2H), 1.75-1.63 (m, 4H), 1.23 (s, 3H); ESI+MS: m/z 236([M+H]⁺).

Example-131: 1-(2-(2-fluorophenoxy)ethyl)-4-methylpiperidin-4-ol

Title compound was prepared from 4-methylpiperidin-4-ol hydrochloride(0.1 g, 0.659 mmol) and Int-2 (Broad-sai-D2R-027) using the generalmethodology of Example-1. Purification using silica gel columnchromatography (3% MeOH/CH₂Cl₂ as eluent) and preparative HPLC to afford0.1 g of 1-(2-(2-fluorophenoxy)ethyl)-4-methylpiperidin-4-ol(Yield=60%). ¹H NMR (400 MHz, CD₃OD): δ 7.14-7.08 (m, 3H), 6.97-6.94 (m,1H), 4.24 (t, J=5.5 Hz, 2H), 2.97-2.95 (m, 2H), 2.81-2.73 (m, 4H),1.74-1.65 (m, 4H), 1.24 (s, 3H); ESI+MS: m/z 254 ([M+H]⁺).

Example-132:4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol

Title compound was prepared from 4-methylpiperidin-4-ol hydrochloride(0.1 g, 0.659 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (50% EtOAc/Hexanesas eluent) to afford 0.06 g of4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(Yield=28%). ¹H NMR (400 MHz, CD₃OD): δ 7.59 (d, J=8.8 Hz, 2H), 7.10 (d,J=9.6 Hz, 2H), 4.24 (t, J=5.6 Hz, 2H), 2.97-2.94 (m, 2H), 2.81-2.68 (m,4H), 1.74-1.64 (m, 4H), 1.24 (s, 3H); ESI+MS: m/z 304 ([M+H]⁺).

Example-133:3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol

tert-butyl(1R,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-oxirane]-8-carboxylate

To a solution of 60% sodium hydride (0.4 g, 16.65 mmol, 1.5 equiv) inDMSO (5 mL) under argon atmosphere was added trimethyl sulfoxoniumiodide (3.66 g, 16.65 mmol, 1.5 equiv) portion wise at room temperature.The reaction was stirred at room temperature for 1 h. To this was addeda solution of (1R,5S)-tert-butyl3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.5 g 11.10 mmol) in DMSO(5 mL) and stirred at room temperature for 24 h. After completion,reaction was diluted with water and extracted with diethyl ether. Theorganic extracts were dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford 2 g of tert-butyl(1R,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-oxirane]-8-carboxylate(Yield=75%)

tert-butyl(1R,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of tert-butyl(1R,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-oxirane]-8-carboxylate (2g, 8.36 mmol) in THF (30 mL) under argon atmosphere was added 1.0 Mtriethyl borohydride solution in THF (10.87 mL, 10.86 mmol, 1.3 equiv)at 0° C. The reaction was stirred at room temperature for 2 h. Aftercompletion, the reaction was diluted with water and extracted withEtOAc. The organic extract was dried over sodium sulphate andconcentrated under reduced pressure. Purification using silica gelcolumn chromatography (15% EtOAc/Hexanes as eluent) to afford 1.6 g oftert-butyl(1R,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate(Yield=79%).

(1R,5S)-3-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride

Title compound was prepared from tert-butyl(1R,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (1.6g, 6.63 mmol) using the general methodology of step 2 of keyIntermediate-VI and the reaction was stirred for 6 h. The crude waswashed with diethyl ether to afford 1 g of(1R,5S)-3-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride(Quantitative).

3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol

Title compound was prepared from(1R,5S)-3-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (1 g, 5.63mmol) using the general methodology of Example-1. Purification usingsilica gel column chromatography (2% MeOH/CH₂Cl₂ as eluent) to afford 1g3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol(Yield=54%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.63-7.59 (m, 2H), 7.27 (d,J=8.4 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H), 4.19 (br s, 2H), 3.92 (br s, 1H),3.24-3.22 (m, 2H), 2.73-2.71 (m, 1H), 2.07 (br s, 2H), 1.75-1.52 (m,6H), 1.00 (s, 3H); ESI+MS: m/z 330 [M+H)⁺].

Example-134:3-Methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-3-ol

Title compound was prepared from 3-methylpiperidin-3-ol hydrochloride(0.1 g, 0.659 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (50% EtOAc/Hexanesas eluent) to afford 0.06 g of3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-3-ol(Yield=29%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.65 (d, J=8.0 Hz, 2H), 7.27(d, J=8.0 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 4.21-4.18 (m, 2H), 4.05 (brs, 1H), 2.75-2.70 (m, 2H), 2.49-2.43 (m, 2H), 2.36-2.26 (m, 2H),1.62-1.58 (m, 1H), 1.43-1.30 (m, 3H), 1.06 (s, 3H); ESI+MS: m/z 304[M+H)⁺.

Example-135:1-(4-Chlorophenyl)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,8-diazaspiro[4.5]decane

tert-butyl 1-(4-chlorophenyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

Title compound was prepared from tert-butyl1,8-diazaspiro[4.5]decane-8-carboxylate (0.1 g, 0.416 mmol) and1-bromo-4-chlorobenzene (0.08 g, 0.416 mmol, 1.0 equiv) using thegeneral methodology of Example 113. Purification using silica gel columnchromatography (30% EtOAc/Hexanes as eluent) to afford 0.1 g oftert-butyl 1-(4-chlorophenyl)-1,8-diazaspiro[4.5]decane-8-carboxylate(Yield=69%). ESI+MS: m/z 351 ([M+H]⁺).

1-(4-Chlorophenyl)-1,8-diazaspiro[4.5]decane hydrochloride

Title compound was prepared from tert-butyl1-(4-chlorophenyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (0.1 g, 0.285mmol) using the general methodology of step 2 of key Intermediate-VI andthe reaction was stirred for 6 h. The crude was triturated with diethylether to afford 0.05 g of 1-(4-chlorophenyl)-1,8-diazaspiro[4.5]decanehydrochloride (Quantitative). ESI+MS: m/z 251.2 ([M+H]⁺).

1-(4-Chlorophenyl)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,8-diazaspiro[4.5]decane

Title compound was prepared from1-(4-chlorophenyl)-1,8-diazaspiro[4.5]decane hydrochloride (0.05 g,0.174 mmol) using the general methodology of Example-1. Purificationusing silica gel column chromatography (3% MeOH/CH₂Cl₂ as eluent)further purified by preparative HPLC to afford 0.03 g of1-(4-chlorophenyl)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,8-diazaspiro[4.5]decane(Yield=39%). ¹H NMR (400 MHz, CD₃OD): δ 7.57-7.53 (m, 2H), 7.18 (d,J=8.4 Hz, 1H), 7.10-7.03 (m, 3H), 6.86 (d, J=9.2 Hz, 2H), 4.25 (t, J=5.6Hz, 2H), 3.31-3.27 (m, 2H), 3.09-3.04 (m, 2H), 2.88 (t, J=5.6 Hz, 2H),2.60 (dt, J=13.2, 4.4 Hz, 2H), 2.37 (dt, J=12.4 Hz, J=4.4 Hz, 2H),2.02-1.98 (m, 2H), 1.93-1.86 (m, 2H), 1.29 (d, J=14.0 Hz, 2H); Ion Trap:m/z: 439 ([M+H]⁺).

Example-136:1-(4-Chlorophenyl)-7-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,7-diazaspiro[3.5]nonane

tert-butyl 1-(4-chlorophenyl)-1,7-diazaspiro[3.5]nonane-7-carboxylate

Title compound was prepared from tert-butyl1,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (0.5 g, 1.90 mmol)and 1-bromo-4-chlorobenzene (0.364 g, 1.903 mmol, 1.0 eq) using thegeneral methodology of Example 113. Purification using silica gel columnchromatography (30% EtOAc/Hexanes as eluent) to afford 0.4 g of1-(4-chlorophenyl)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,8-diazaspiro[4.5]decane(Yield=62%).

1-(4-Chlorophenyl)-1,7-diazaspiro[3.5]nonane hydrochloride

Title compound was prepared from tert-butyl1-(4-chlorophenyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (0.45 g,1.336 mmol) using the general methodology of step 2 of keyIntermediate-VI to afford 0.3 g of1-(4-chlorophenyl)-1,7-diazaspiro[3.5]nonane hydrochloride(Quantitative).

1-(4-Chlorophenyl)-7-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,7-diazaspiro[3.5]nonane

Title compound was prepared from1-(4-chlorophenyl)-1,7-diazaspiro[3.5]nonane hydrochloride (0.15 g,0.549 mmol) using the general methodology of Example-1. Purificationusing silica gel column chromatography (3% MeOH/CH₂Cl₂ as eluent)followed by preparative HPLC purification to afford 0.02 g of1-(4-chlorophenyl)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,8-diazaspiro[4.5]decane(Yield=9%). ¹H NMR (400 MHz, CD₃OD): δ 7.59-7.55 (m, 2H), 7.19 (d, J=8.8Hz, 1H), 7.11-7.05 (m, 3H), 6.50 (d, J=8.8 Hz, 2H), 4.26 (t, J=5.6 Hz,2H), 3.67 (t, J=7.2 Hz, 2H), 3.08-3.06 (m, 2H), 2.89 (t, J=5.6 Hz, 2H),2.30 (d, J=9.2 Hz, 4H), 2.16 (t, J=7.2 Hz, 2H), 1.73 (d, J=9.2 Hz, 2H);ESI+MS: m/z: 425 ([M+H]⁺).

Example-137:1-(4-chlorophenyl)-7-(2-(2-fluorophenoxy)ethyl)-1,7-diazaspiro[3.5]nonane

Title compound was prepared from1-(4-chlorophenyl)-1,7-diazaspiro[3.5]nonane hydrochloride (0.15 g, 0.54mmol) using the general methodology of Example-1. Purification usingsilica gel column chromatography (3% MeOH/CH₂Cl₂ as eluent) followed bypreparative HPLC purification to afford 0.02 g of1-(4-chlorophenyl)-7-(2-(2-fluorophenoxy)ethyl)-1,7-diazaspiro[3.5]nonane(Yield=10%). ¹H NMR (400 MHz, CD₃OD): δ 7.11-7.06 (m, 5H), 6.95-6.90 (m,1H), 6.51 (d, J=8.8 Hz, 2H), 4.20 (t, J=5.6 Hz, 2H), 3.67 (t, J=7.6 Hz,2H), 3.07 (d, J=9.6 Hz, 2H), 2.85 (t, J=5.6 Hz, 2H), 2.36-2.23 (m, 4H),2.16 (t, J=7.2 Hz, 2H), 1.74 (d, J=10.4 Hz, 2H); ESI+MS: m/z: 375([M+H]⁺).

Example-138:4-methyl-1-(3-(2-(trifluoromethyl)phenoxy)propyl)piperidin-4-ol

Title compound was prepared from 4-methylpiperidin-4-ol hydrochloride(0.1 g 0.659 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (3% MeOH/CH₂Cl₂ aseluent) to afford 0.07 g of4-methyl-1-(3-(2-(trifluoromethyl)phenoxy)propyl)piperidin-4-ol(Yield=33%). ¹H NMR (400 MHz, CD₃OD): δ 7.55-7.51 (m, 2H), 7.14 (d,J=8.4 Hz, 1H), 7.02 (t, J=7.6 Hz, 1H), 4.12 (t, J=6.0 Hz, 2H), 2.65-2.61(m, 4H), 2.54-2.48 (m, 2H), 2.06-1.99 (m, 2H), 1.65-1.62 (m, 4H), 1.20(s, 3H); ESI+MS: m/z: 318 ([M+H]⁺).

Example-139:3-Methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)pyrrolidin-3-ol

Title compound was prepared from 3-methylpyrrolidin-3-ol hydrochloride(0.3 g, 2.18 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (2% MeOH/CH₂Cl₂ aseluent) to afford 0.12 g of3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)pyrrolidin-3-ol(Yield=19%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.60 (t, J=8.0 Hz, 2H), 7.26(d, J=8.5 Hz, 1H), 7.08 (t, J=8.0 Hz, 1H), 4.50 (br s, 1H) 4.17 (t,J=6.0 Hz, 2H), 2.82-2.80 (m, 2H), 2.71-2.55 (m, 4H), 1.73-1.65 (m, 2H),1.22 (s, 3H); ESI+MS: m/z: 290 [M+H].

Example-140:1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-ol

Title compound was prepared from 4-methylpiperidin-4-ol hydrochloride(0.20 g, 1.32 mmol) using the general methodology of Example-1.Purification using preparative HPLC afforded 0.05 g of1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-ol(Yield=15%). ¹H NMR (400 MHz, DMSO-d₆): δ 6.82 (m, 4H), 4.29 (m, 2H),4.07 (s, 1H), 3.92 (m, 1H), 2.53 (m, 3H), 2.42 (m, 3H), 1.45 (m, 4H),1.09 (s, 3H); ESI+MS: m/z: 264 ([M+H]⁺). The enantiomers of 140 wereseparated using chiral HPLC (method D) and afforded the pure enantiomers140a and 140b.

Example-141:4-methyl-1-(2-(2-(methylsulfonyl)phenoxy)ethyl)-4-phenoxypiperidine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.1 g, 0.44 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) to afford 0.025 g of4-methyl-1-(2-(2-(methylsulfonyl)phenoxy)ethyl)-4-phenoxypiperidine(Yield=15%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.80-7.78 (m, 1H), 7.68-7.64(m, 1H), 7.31-7.25 (m, 3H), 7.14 (t, J=8.0 Hz, 1H), 7.06-6.97 (m, 3H),4.27 (t, J=4 Hz, 2H), 3.37 (s, 3H), 2.58-2.49 (m, 6H), 1.87-1.84 (m,2H), 1.61-1.55 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 390 ([M+H]⁺).

Example-142:4-(4-chlorophenoxy)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using preparative HPLC afforded 0.015 g of4-(4-chlorophenoxy)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidine(Yield=21%). ¹H NMR (400 MHz, CD₃OD): δ 7.32 (m, 2H), 7.02 (m, 2H), 6.83(m, 4H), 4.31 (m, 2H), 3.95 (m, 1H), 2.57 (m, 6H), 1.87 (m, 2H), 1.64(m, 2H), 1.24 (s, 3H); ESI+MS: m/z 374 ([M+H]⁺). The enantiomers of 142were separated using chiral HPLC (method D) and afforded the pureenantiomers 142a and 142b.

Example-143:4-(4-chlorophenoxy)-1-(2-(cyclohexyloxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.1 g, 0.38 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) afforded 0.05 g of4-(4-chlorophenoxy)-1-(2-(cyclohexyloxy)ethyl)-4-methylpiperidine(Yield=37%). ¹H NMR (500 MHz, CD₃OD): δ 7.27-7.26 (d, J=8.5 Hz, 2H),7.00 (d, J=4.5 Hz, 2H), 3.67 (t, J=5.5 Hz, 2H), 3.32-3.20 (m, 1H),2.78-2.74 (m, 6H), 2.03-2.01 (m, 2H), 1.93-1.91 (m, 2H), 1.78-1.72 (m,4H), 1.85-1.75 (m, 1H), 1.33-1.27 (m, 8H); ESI+MS: m/z 352 ([M+H]⁺).

Example-144:5-chloro-1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine]

1-(2-phenoxyethyl)pyrrolidin-3-ol

Title compound was prepared from pyrrolidin-3-ol hydrochloride (2.0 g,16.2 mmol) using the general methodology of Example-1. Purificationusing silica gel column chromatography (2% MeOH/CH₂Cl₂ as eluent)afforded 2.41 g of 1-(2-phenoxyethyl)pyrrolidin-3-ol (Yield=72%).

1-(2-phenoxyethyl)pyrrolidin-3-one

A solution of DMSO (1.1 mL, 14.5 mmol) in anhydrous DCM (10 ml) underargon was cooled to −78° C. A solution of oxalyl chloride (0.62 mL, 7.24mmol) in DCM (5 ml) was added dropwise and the mixture was stirred at−78° C. for 1 h. A solution of 1-(2-phenoxyethyl)pyrrolidin-3-ol (1.0 g,4.82 mmol) in DCM (7 ml) was then added dropwise over 30 minutes and themixture was stirred for 3 h at −78° C. Then, triethylamine (2.7 mL, 19.3mmol) was added and the reaction mixture was stirred at RT for 1 hour.Water (20 mL) was added and the organic layer separated. The aqueousphase was extracted twice with DCM (10 mL). The combined organicextracts were dried over sodium sulfate, filtered and concentrated.Purification using silica gel chromatography using a gradient of MeOH inDCM afforded 620 mg of 1-(2-phenoxyethyl)pyrrolidin-3-one (Yield=63%).ESI+MS: m/z 206 ([M+H]⁺).

3-(5-chloro-2-fluorobenzyl)-1-(2-phenoxyethyl)pyrrolidin-3-ol

Magnesium turnings (53 mg, 2.19 mmol) and a crystal of iodine in diethylether (1 ml) were placed under Argon atmosphere and the mixture waswarmed to 35° C. When color disappeared,2-(bromomethyl)-4-chloro-1-fluorobenzene (408 mg, 1.83 mmol) in diethylether (0.5 ml) was added dropwise. The reaction mixture was kept at 35°C. overnight. A solution of 1-(2-phenoxyethyl)pyrrolidin-3-one (250 mg,1.22 mmol) in 1.5 ml of diethyl ether was added dropwise over 15minutes. At the end of the addition, the reaction mixture was stirredfor 2 h at RT. The reaction mixture was then extracted with ethylacetate and aq.NH₄Cl. The organic layer was dried over Na₂SO₄, filteredand concentrated. Purification using silica gel chromatography using agradient of ethyl acetate in hexanes afforded 210 mg of3-(5-chloro-2-fluorobenzyl)-1-(2-phenoxyethyl)pyrrolidin-3-ol(Yield=50%). ESI+MS: m/z 350 ([M+H]⁺).

5-chloro-1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine]

3-(5-chloro-2-fluorobenzyl)-1-(2-phenoxyethyl)pyrrolidin-3-ol (75 mg,0.21 mmol) was dissolved in DMF/Toluene 1/1 (10 mL) under argon. NaH (14mg, 0.34 mmol) was added in 1 portion and the mixture was stirred at 90°C. After 15 h, reaction was complete and extracted with ethyl acetateand aq.NH₄Cl. The organic layer was dried on Na₂SO₄, filtered andconcentrated under reduced pressure. Purification using a gradient ofDCM/MeOH afforded 29 mg of5-chloro-1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine](Yield=41%). ¹H NMR (300 MHz, CDCl₃): δ 7.27 (t, J=7.5 Hz, 2H),7.15-7.00 (m, 2H), 7.00-6.85 (m, 3H), 6.68 (d, J=8.4 Hz, 1H), 4.12 (t,J=5.5 Hz, 2H), 3.30-3.10 (m, 3H), 3.05 (m, 1H), 2.96 (t, J=5.3 Hz, 2H),2.85-2.70 (m, 2H), 2.40-2.30 (m, 1H), 2.10-2.00 (m, 1H); ESI+MS: m/z 330([M+H]⁺).

Example-145:(3aS,9aR)-7-chloro-2-(2-phenoxyethyl)-1,2,3,3a,9,9a-hexahydrochromeno[2,3-c]pyrrole

(3R,4S)-tert-butyl3-(5-chloro-2-fluorobenzyl)-4-hydroxypyrrolidine-1-carboxylate

To magnesium turnings (41 mg, 1.7 mmol) in diethyl ether (1 ml) underArgon atmosphere was added a crystal of iodine and the mixture waswarmed to 35° C. When color disappeared,2-(bromomethyl)-4-chloro-1-fluorobenzene (317 mg, 1.42 mmol) in diethylether (0.7 ml) was added dropwise over 15 minutes. The reaction mixturewas kept at 35° C. overnight. Copper (I) bromide dimethylsulfide complex(19.4 mg, 0.094 mmol) was added and the solution turned dark brownrapidly. The solution was stirred at 35° C. for 1 h. Then, a solution oftert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (175 mg, 0.95mmol) in diethyl ether (1 ml) was added dropwise and stirring wascontinued at 35° C. After 1 hour, the reaction mixture was extractedwith ethyl acetate/aq.NH₄Cl. The organic layer was dried over Na₂SO₄,filtered and concentrated. Purification using silica gel columnchromatography and a gradient of ethyl acetate in hexanes as eluentafforded 77 mg of (3R,4S)-tert-butyl3-(5-chloro-2-fluorobenzyl)-4-hydroxypyrrolidine-1-carboxylate(Yield=25%).

(3aS,9aR)-tert-butyl7-chloro-3,3a,9,9a-tetrahydrochromeno[2,3-c]pyrrole-2(1H)-carboxylate

(3R,4S)-tert-butyl3-(5-chloro-2-fluorobenzyl)-4-hydroxypyrrolidine-1-carboxylate (75 mg,0.23 mmol) was dissolved in DMF/Toluene 1/1 mixture (1.2 mL) and placedunder argon. NaH (15 mg, 0.37 mmol) was added in 1 portion and themixture was stirred at 90° C. overnight. The reaction mixture wasextracted with ethyl acetate and aq.NH₄Cl, the organic layer was driedover Na₂SO₄, filtered and concentrated. Purification using silica gelcolumn chromatography and a gradient of ethyl acetate in hexanes aseluent afforded 24 mg of (3aS,9aR)-tert-butyl7-chloro-3,3a,9,9a-tetrahydrochromeno[2,3-c]pyrrole-2(1H)-carboxylate(Yield=34%).

(3aS,9aR)-7-chloro-1,2,3,3a,9,9a-hexahydrochromeno[2,3-c]pyrroletrifluoroacetic acid salt

(3aS,9aR)-tert-butyl7-chloro-3,3a,9,9a-tetrahydrochromeno[2,3-c]pyrrole-2(1H)-carboxylate(24 mg, 0.08 mmol) was dissolved in DCM (0.8 mL) under argon and TFA (88mg, 0.78 mmol) was added dropwise at RT. After 3 h, solvents wereevaporated and then coevaporate with toluene twice. The crude was usedin the next step without further purification (Yield=quantitative).ESI+MS: m/z 210 ([M+H]⁺).

(3aS,9aR)-7-chloro-2-(2-phenoxyethyl)-1,2,3,3a,9,9a-hexahydrochromeno[2,3-c]pyrrole

Title compound was prepared from(3aS,9aR)-7-chloro-1,2,3,3a,9,9a-hexahydrochromeno[2,3-c]pyrroletrifluoroacetic acid salt (25 mg, 0.08 mmol) using the generalmethodology of Example-1. Purification using silica gel columnchromatography (5% MeOH/CH₂Cl₂ as eluent) afforded 16 mg of(3aS,9aR)-7-chloro-2-(2-phenoxyethyl)-1,2,3,3a,9,9a-hexahydrochromeno[2,3-c]pyrrole(Yield=63%). ¹H NMR (300 MHz, CDCl₃): δ 7.33-7.24 (m, 2H), 7.10-7.03 (m,2H), 7.00-6.88 (m, 3H), 6.82-6.75 (m, 1H), 4.15-3.95 (m, 3H), 3.32-3.22(m, 2H), 3.18-2.95 (m, 3H), 2.86 (dd, J=15.8 Hz, J=5.2 Hz, 1H),2.77-2.63 (m, 2H), 2.40-2.20 (m, 1H); ESI+MS: m/z 330 ([M+H]⁺).

Example-146:4-(4-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethoxy)phenoxy)ethyl)piperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.07 g, 0.27 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.05 g of4-(4-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethoxy)phenoxy)ethyl)piperidine(Yield=44%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.35-7.24 (m, 5H), 7.02-6.98(m, 3H), 4.16 (t, J=5.6 Hz, 2H), 2.74 (t, J=5.6 Hz, 2H), 2.60-2.57 (m,4H), 1.86-1.83 (m, 2H), 1.64-1.57 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 430([M+H]⁺).

Example-147:5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) afforded 0.05 g of5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine(Yield=63%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.44 (d, J=2.4 Hz, 1H), 7.82(d, J=8.4 Hz, 1H), 7.62 (dd, J=8.8 Hz, J=2.8 Hz, 1H), 7.33-7.29 (m, 2H),7.02-6.99 (m, 2H), 4.25 (t, J=5.6 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H),2.58-2.55 (m, 4H), 1.88-1.83 (m, 2H), 1.65-1.58 (m, 2H), 1.24 (s, 3H);ESI+MS: m/z 415 ([M+H]⁺).

Example-148:2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-5-(trifluoromethyl)pyridine

Title compound was prepared from2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethanol (0.45 g, 1.67mmol) and 2-bromo-5-(trifluoromethyl)pyridine (0.75 g, 3.34 mmol) usingthe general methodology of step 2 of key intermediate-I. Purificationusing preparative HPLC afforded 0.02 g of2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-5-(trifluoromethyl)pyridine(Yield=3%). ¹H NMR (400 MHz, CD₃OD): δ 8.46-8.45 (m, 1H), 7.94-7.91 (m,1H), 7.25-7.22 (m, 2H), 6.99-6.93 (m, 3H), 4.56 (t, J=5.6 Hz, 2H), 2.87(t, J=5.6 Hz, 2H), 2.75-2.67 (m, 4H), 2.02-1.97 (m, 2H), 1.76-1.69 (m,2H), 1.27 (s, 3H); ESI+MS: m/z 415 ([M+H]⁺).

Example-149:4-(4-chlorophenoxy)-1-(2-(4-fluorophenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.10 g, 0.38 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) afforded 0.08 g of4-(4-chlorophenoxy)-1-(2-(4-fluorophenoxy)ethyl)-4-methylpiperidine(Yield=58%). ¹H NMR (400 MHz, CD₃OD): δ 7.26-7.22 (m, 2H), 7.01-6.96 (m,4H), 6.94-6.90 (m, 2H), 4.11 (t, J=5.6 Hz, 2H), 2.85 (t, J=5.6 Hz, 2H),2.76-2.67 (m, 4H), 2.03-1.98 (m, 2H), 1.77-1.70 (m, 2H), 1.28 (s, 3H);ESI+MS: m/z 364 ([M+H]⁺).

Example-150:4-(4-chlorophenoxy)-4-methyl-1-(2-(p-tolyloxy)ethyl)piperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) afforded 0.05 g of4-(4-chlorophenoxy)-4-methyl-1-(2-(p-tolyloxy)ethyl)piperidine(Yield=73%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.32-7.29 (m, 2H), 7.07-6.99(m, 4H), 6.81 (d, J=8.4 Hz, 2H), 4.02 (t, J=6.0 Hz, 2H), 2.69 (t, J=5.6Hz, 2H), 2.56-2.54 (m, 4H), 2.22 (s, 3H), 1.87-1.84 (m, 2H), 1.65-1.59(m, 2H), 1.23 (s, 3H); ESI+MS: m/z 360 ([M+H]⁺).

Example-151:4-(4-chlorophenoxy)-1-(2-(4-chlorophenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) afforded 0.05 g of4-(4-chlorophenoxy)-1-(2-(4-chlorophenoxy)ethyl)-4-methylpiperidine(Yield=69%). ¹H NMR (400 MHz, CD₃OD): δ 7.27-7.23 (m, 4H), 7.00-6.96 (m,2H), 6.93-6.90 (m, 2H), 4.13 (t, J=5.6 Hz, 2H), 2.86 (t, J=5.6 Hz, 2H),2.76-2.68 (m, 4H), 2.04-1.97 (m, 2H), 1.78-1.71 (m, 2H), 1.28 (s, 3H);ESI+MS: m/z 381 ([M+H]⁺).

Example-152:4-(4-chlorophenoxy)-4-methyl-1-(2-(4-(methylsulfonyl)phenoxy)ethyl)piperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) afforded 0.05 g of4-(4-chlorophenoxy)-4-methyl-1-(2-(4-(methylsulfonyl)phenoxy)ethyl)piperidine(Yield=62%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.82 (d, J=9.2 Hz, 2H), 7.31(d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 7.01 (d, J=9.2 Hz, 2H), 4.19(t, J=5.6 Hz, 2H), 3.14 (s, 3H), 2.74 (t, J=5.6 Hz, 2H), 2.58-2.55 (m,4H), 1.87-1.84 (m, 2H), 1.66-1.59 (m, 2H), 1.24 (s, 3H); ESI+MS: m/z 424([M+H]⁺).

Example-153:1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethanone

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.20 g, 0.76 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) afforded 0.20 g of1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethanone(Yield=68%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.92-7.89 (m, 2H), 7.33-7.29(m, 2H), 7.05-6.99 (m, 4H), 4.17 (t, J=6.0 Hz, 2H), 2.74 (t, J=5.6 Hz,2H), 2.57-2.52 (m, 4H), 2.51-2.50 (m, 3H), 1.87-1.84 (m, 2H), 1.66-1.59(m, 2H), 1.23 (s, 3H); ESI+MS: m/z 388 ([M+H]⁺).

Example-154:1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethanol

Title compound was prepared from1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethanone(0.10 g, 0.26 mmol) using the general methodology of Example 107.Purification using silica gel column chromatography (3% MeOH/CH₂Cl₂ aseluent) afforded 0.50 g of1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethanol(Yield=50%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.33-7.29 (m, 2H), 7.24-7.21(m, 2H), 7.03-6.99 (m, 2H), 6.88-6.85 (m, 2H), 4.99 (t, J=4.0 Hz, 1H),4.67-4.62 (m, 1H), 4.06-4.02 (m, 2H), 2.72-2.70 (m, 2H), 2.56-2.50 (m,4H), 1.87-1.84 (m, 2H), 1.64-1.62 (m, 2H), 1.28 (d, J=6.4 Hz, 3H), 1.24(s, 3H); ESI+MS: m/z 390 ([M+H]⁺).

Example-155:2-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)propan-2-ol

Title compound was prepared from1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethanone(0.10 g, 0.26 mmol) using the general methodology of step 1 of keyintermediate-I. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.50 g of2-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)propan-2-ol(Yield=29%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.35-7.29 (m, 4H), 7.00 (d,J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 4.86 (s, 1H), 4.04 (t, J=6.0 Hz,2H), 2.70 (t, J=6.0 Hz, 2H), 2.55-2.50 (m, 4H), 1.88-1.83 (m, 2H),1.65-1.59 (m, 2H), 1.37 (s, 6H), 1.23 (s, 3H); ESI+MS: m/z 404 ([M+H]⁺).

Example-156:4-(4-chlorophenoxy)-1-(2-(3-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethanol (0.10 g, 0.37mmol) and 1,3-difluoro-2-(trifluoromethyl)benzene (68 mg, 0.37 mmol)using the general methodology of step 2 of key intermediate-I.Purification using preparative HPLC afforded 0.035 g of4-(4-chlorophenoxy)-1-(2-(3-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine(Yield=22%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.66-7.60 (m, 1H), 7.32-7.28(m, 2H), 7.13 (d, J=8.4 Hz, 1H), 7.02-6.94 (m, 3H), 4.22 (t, J=5.6 Hz,2H), 2.74 (t, J=5.6 Hz, 2H), 2.59-2.49 (m, 4H), 1.85-1.82 (m, 2H),1.63-1.56 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 432 ([M+H]⁺).

Example-157:4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.20 g, 0.76 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (2%MeOH/CH₂Cl₂ as eluent) afforded 0.16 g of4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine(Yield=49%). ¹H NMR (400 MHz, CD₃OD): δ 7.36-7.30 (m, 2H), 7.27-7.19 (m,3H), 7.00-6.96 (m, 2H), 4.25 (t, J=5.6 Hz, 2H), 2.92 (t, J=5.6 Hz, 2H),2.80-2.76 (m, 4H), 2.03-1.97 (m, 2H), 1.76-1.69 (m, 2H), 1.28 (s, 3H);ESI+MS: m/z 432 ([M+H]⁺).

Example-158:4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-(methylsulfonyl)phenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.10 g, 0.38 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) afforded 0.07 g of4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-(methylsulfonyl)phenoxy)ethyl)-4-methylpiperidine(Yield=42%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.59-7.52 (m, 2H), 7.37-7.29(m, 3H), 7.03-6.99 (m, 2H), 4.25 (t, J=4.8 Hz, 2H), 3.38 (s, 3H), 2.75(t, J=5.6 Hz, 2H), 2.57-2.55 (m, 4H), 1.86-1.81 (m, 2H), 1.61-1.55 (m,2H), 1.23 (s, 3H); ESI+MS: m/z 442 ([M+H]⁺).

Example-159:4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.10 g, 0.38 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.07 g of4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine(Yield=40%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.33-7.29 (m, 2H), 7.03-6.99(m, 2H), 6.91-6.89 (m, 2H), 6.67 (dt, J=11.6 Hz, J=3.2 Hz, 1H), 4.06 (t,J=5.6 Hz, 2H), 3.72 (s, 3H), 2.73-2.70 (m, 2H), 2.57-2.55 (m, 4H),1.86-1.83 (m, 2H), 1.65-1.58 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 394([M+H]⁺).

Example-160:4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.12 g, 0.46 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.07 g of4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine(Yield=39%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.27-7.23 (m, 2H), 7.02-6.92(m, 3H), 6.77 (dd, J=10.4 Hz, J=3.2 Hz, 1H), 6.61-6.56 (m, 1H), 4.12 (t,J=5.6 Hz, 2H), 3.83 (s, 3H), 2.87-2.84 (m, 2H), 2.79-2.70 (m, 4H),2.00-1.97 (m, 2H), 1.77-1.70 (m, 2H), 1.28 (s, 3H); ESI+MS: m/z 394([M+H]⁺).

Example-161:5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)thiazole

Na-metal (34 mg, 1.48 mmol) was added to2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethanol (0.20 g, 0.74mmol) and the mixture was heated at 120° C. for 5 h. Then 5-bromothiazole (195 mg, 1.19 mmol) was added and the reaction mixture washeated at 80° C. for 48 h. The reaction mixture was cooled to RT,quenched with water and extracted with EtOAc. The organic layer wasseparated, dried over Na₂SO₄ and concentrated under reduced pressure.The crude compound was purified by column chromatography eluting with 2%MeOH in DCM and further purified by preparative HPLC to obtain 5 mg of5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)thiazole (Yield2%). ¹HNMR (400 MHz, CD₃OD): δ 8.35 (s, 1H), 7.25-7.22 (m, 3H), 6.97 (d,J=8.8 Hz, 2H), 4.26 (t, J=5.2 Hz, 2H), 2.87 (t, J=5.2 Hz, 2H), 2.72-2.70(m, 4H), 2.0-1.98 (m, 2H), 1.77-1.69 (m, 2H), 1.27 (s, 3H); ESI+MS: m/z353 ([M+H]⁺).

Example-162:2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine

Title compound was prepared from2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethanol (0.10 g, 0.37mmol) and 2-chloro-3-(trifluoromethyl)pyridine (135 mg, 0.74 mmol) usingthe general methodology of step 2 of key intermediate-I. Purificationusing preparative HPLC afforded 0.05 g of2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine(Yield=33%). ¹H NMR (400 MHz, CD₃OD): δ 8.35 (dd, J=4.8 Hz, J=1.2 Hz,1H), 7.98 (dd, J=7.6 Hz, J=0.8 Hz, 1H), 7.26-7.22 (m, 2H), 7.10-7.07 (m,1H), 6.99-6.95 (m, 2H), 4.62 (t, J=5.6 Hz, 2H), 2.90 (t, J=6.0 Hz, 2H),2.77-2.74 (m, 4H), 2.01-1.97 (m, 2H), 1.75-1.68 (m, 2H), 1.27 (s, 3H);ESI+MS: m/z 415 ([M+H]⁺).

Example-163:3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.07 g, 0.46 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.07 g of3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine(Yield=63%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.24 (d, J=4.4 Hz, 1H), 7.82(d, J=8.4 Hz, 1H), 7.69-7.66 (m, 1H), 7.32-7.29 (m, 2H), 7.02-6.97 (m,2H), 4.28 (t, J=5.6 Hz, 2H), 2.75 (t, J=5.6 Hz, 2H), 2.59-2.56 (m, 4H),1.85-1.81 (m, 2H), 1.62-1.55 (m, 2H), 1.22 (s, 3H); ESI+MS: m/z 415([M+H]⁺).

Example-164:2-((4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)pyridine

tert-butyl 4-methyl-4-(pyridin-2-yloxy)piperidine-1-carboxylate

Title compound was prepared from tert-butyl4-hydroxy-4-methylpiperidine-1-carboxylate (0.50 g, 2.32 mmol) and2-bromopyridine (0.73 g, 4.64 mmol) using the general methodology ofExample 61. Purification using silica gel column chromatography (2%EA/Hexanes) afforded 0.20 g of tert-butyl4-methyl-4-(pyridin-2-yloxy)piperidine-1-carboxylate (Yield=30%).

2-((4-methylpiperidin-4-yl)oxy)pyridine hydrochloride

Title compound was prepared from tert-butyl4-methyl-4-(pyridin-2-yloxy)piperidine-1-carboxylate (0.2 g, 0.68 mmol)using general methodology of step 2 of key intermediate-VI to afford0.12 g of 2-((4-methylpiperidin-4-yl)oxy)pyridine hydrochloride(Yield=77%).

2-((4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)pyridine

Title compound was prepared from 2-((4-methylpiperidin-4-yl)oxy)pyridinehydrochloride (0.12 g, 0.53 mmol) using the general methodology ofExample-1. Purification using preparative HPLC afforded 0.05 g of2-((4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)pyridine(Yield=25%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.10-8.08 (m, 1H), 7.66-7.61(m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.92-6.89 (m, 1H), 6.72 (d, J=8.0 Hz,1H), 4.14 (t, J=6.0 Hz, 2H), 2.70-2.66 (m, 2H), 2.64-2.59 (m, 2H),2.40-2.34 (m, 2H), 2.34-2.27 (m, 2H), 1.74-1.68 (m, 2H), 1.57 (s, 3H);ESI+MS: m/z 381 ([M+H]⁺).

Example-165:1-(2-(5-chloro-2-(trifluoromethyl)phenoxy)ethyl)-4-(4-chlorophenoxy)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) afforded 0.05 g of1-(2-(5-chloro-2-(trifluoromethyl)phenoxy)ethyl)-4-(4-chlorophenoxy)-4-methylpiperidine(Yield=59%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.61 (d, J=8.0 Hz, 1H), 7.43(m, 1H), 7.32-7.28 (m, 2H), 7.15 (dd, J=1.2 Hz, J=8.4 Hz, 1H), 7.02-6.98(m, 2H), 4.25 (t, J=5.6 Hz, 2H), 2.73 (t, J=5.6 Hz, 2H), 2.59-2.55 (m,4H), 1.86-1.80 (m, 2H), 1.62-1.56 (m, 2H), 1.22 (s, 3H); ESI+MS: m/z 449([M+H]⁺).

Example-166:7-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.07 g, 0.27 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) afforded 0.05 g of7-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one(Yield=45%). ¹H NMR (400 MHz, CD₃OD): δ 7.28-7.22 (m, 2H), 7.07 (d,J=8.4 Hz, 1H), 7.02-6.96 (m, 2H), 6.58 (dd, J=8.0 Hz, J=2.4 Hz, 1H),6.48 (d, J=2.4 Hz, 1H), 4.12 (t, J=5.2 Hz, 2H), 2.89-2.84 (m, 4H),2.80-2.67 (m, 4H), 2.54 (dd, J=8.4 Hz, J=6.8 Hz, 2H), 2.04-1.98 (m, 2H),1.78-1.70 (m, 2H), 1.29 (s, 3H); ESI+MS: m/z 415 ([M+H]⁺).

Example-167:4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) followed by preparative HPLC afforded 0.015 g of4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine(Yield=19%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.64 (m, 2H), 7.36 (d,J=6.0 Hz, 1H), 7.35-7.27 (m, 2H), 7.02-6.97 (m, 2H), 4.33 (t, J=5.6 Hz,2H), 2.77 (t, J=5.6 Hz, 2H), 2.65-2.55 (m, 4H), 1.87-1.80 (m, 2H),1.65-1.55 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 415 ([M+H]⁺).

Example-168:N-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-2-(trifluoromethyl)aniline

To a solution of2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-N-(2-(trifluoromethyl)phenyl)acetamide (0.05 g, 0.12 mmol) in dry THF (5 mL) were added NaBH₄ (0.044g, 1.17 mmol) and 12 (0.21 g, 0.82 mmol) at 0° C. The mixture wasstirred at 80° C. for 16 h. Solvents were evaporated and the crudereaction mass was diluted with water and extracted with ethyl acetate.The organic layer was dried with Na₂SO₄, filtered and concentrated.Purification using silica gel column chromatography (5% MeOH/CH₂Cl₂ aseluent) afforded 0.012 g ofN-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-2-(trifluoromethyl)aniline(Yield=25%). ¹H NMR (400 MHz, CD₃OD): δ 7.43-7.35 (m, 2H), 7.27-7.22 (m,2H), 7.02-6.96 (m, 2H), 6.82 (d, J=8.4 Hz, 1H), 6.7 (t, J=7.6 Hz, 1H),3.35-3.25 (m, 2H), 2.70 (t, J=6.0 Hz, 2H), 2.67-2.60 (m, 4H), 2.06-1.96(m, 2H), 1.75-1.68 (m, 2H), 1.28 (s, 3H); ESI+MS: m/z 413 ([M+H]⁺).

Example-169:N-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-N-methyl-2-(trifluoromethyl)aniline

To a stirred solution ofN-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-2-(trifluoromethyl)aniline(100 mg, 0.24 mmol) in MeOH (10 mL) were added HCHO (11 mg, 0.36 mmol)and NaCNBH₃ (45 mg, 0.72 mmol) at 0° C. The reaction mixture was stirredat RT for 48 h. After 48 h, HCHO (11 mg, 0.36 mmol) and NaCNBH₃ (45 mg,0.72 mmol) were added at 0° C. and the reaction mixture was stirred atRT for 4 days. After completion of the reaction (monitored by LCMS),volatiles were removed under reduced pressure. The residue was basifiedwith sat. aq. NaHCO₃ and extracted with DCM. The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure.Purification using silica gel column chromatography (50% EA/Hexanes aseluent) followed by preparative HPLC afforded 0.016 g ofN-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-N-methyl-2-(trifluoromethyl)aniline(Yield=15%). ¹H NMR (400 MHz, CD₃OD): δ 7.65-7.50 (m, 3H), 7.31-7.22 (m,3H), 7.00-6.93 (m, 2H), 3.17-3.10 (m, 2H), 2.70 (s, 3H), 2.65-2.50 (m,6H), 2.00-1.92 (m, 2H), 1.73-1.63 (m, 2H), 1.26 (s, 3H); ESI+MS: m/z 427([M+H]⁺).

Example-170:N-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-N-(2-(trifluoromethyl)phenyl)acetamide

To a stirred solution ofN-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-2-(trifluoromethyl)aniline(50 mg, 0.12 mmol) in DCM (5 mL) were added pyridine (2 mL, 24.7 mmol)and acetyl chloride (0.026 mL, 0.36 mmol) at 0° C. The reaction mixturewas stirred at RT for 12 h. After completion of the reaction (monitoredby LCMS), the mixture was diluted in water and extracted with DCM. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Purification using preparative HPLC afforded 0.020 gofN-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-N-(2-(trifluoromethyl)phenyl)acetamide (Yield=36%). ¹H NMR (400 MHz, CD₃OD): δ 7.94-7.80 (m, 2H),7.75-7.62 (m, 2H), 7.34 (d, J=9.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H),4.47-4.37 (m, 2H), 3.48-3.20 (m, 6H), 2.14-2.02 (m, 2H), 1.95-1.80 (m,2H), 1.70 (s, 3H), 1.35-1.25 (m, 3H); ESI+MS: m/z 455 ([M+H]⁺).

Example-171:2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-8-(trifluoromethyl)quinoline

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.01 g of2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-8-(trifluoromethyl)quinoline(Yield=11%). ¹H NMR (400 MHz, CD₃OD): δ 8.22 (d, J=9.2 Hz, 1H),8.05-7.99 (m, 2H), 7.49 (t, J=8.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.07 (d,J=8.8 Hz, 1H), 6.99-6.95 (m, 2H), 4.72 (t, J=6.0 Hz, 2H), 2.97 (t, J=6.0Hz, 2H), 2.78-2.73 (m, 4H), 2.04-1.98 (m, 2H), 1.77-1.71 (m, 2H), 1.28(s, 3H); ESI+MS: m/z 465 ([M+H]⁺).

Example-172:1-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-8-(trifluoromethyl)quinolin-2(1H)-one

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using preparative HPLC afforded 0.004 g of1-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-8-(trifluoromethyl)quinolin-2(1H)-one(Yield=6%). ¹H NMR (400 MHz, CD₃OD): δ 7.98 (dd, J=8.0 Hz, J=1.6 Hz,1H), 7.89-7.86 (m, 2H), 7.41 (t, J=8.0 Hz, 1H), 7.23-7.19 (m, 2H),6.89-6.85 (m, 2H), 6.68 (d, J=9.2 Hz, 1H), 4.54 (t, J=6.0 Hz, 2H), 2.53(t, J=6.0 Hz, 2H), 2.44-2.38 (m, 2H), 2.30-2.25 (m, 2H), 1.67-1.62 (m,2H), 1.31-1.25 (m, 2H), 1.28 (s, 3H); ESI+MS: m/z 465 ([M+H]⁺).

Example-173: 4-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)pyridine

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.10 g, 0.44 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) afforded 0.015 g of4-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)pyridine (Yield=11%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.78 (d, J=6.4 Hz, 2H), 7.53 (d, J=6.4 Hz,2H), 7.32 (t, J=8.0 Hz, 2H), 7.13-7.06 (m, 3H), 4.73-4.70 (m, 2H),3.72-3.42 (m, 6H), 2.12-2.09 (m, 2H), 1.97-1.91 (m, 2H), 1.26 (s, 3H);ESI+MS: m/z 313 ([M+H]⁺).

Example-174: 2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)pyridine

Title compound was prepared from2-(4-methyl-4-phenoxypiperidin-1-yl)ethanol (0.15 g, 0.64 mmol) and2-bromopyridine (151 mg, 0.96 mmol) using the general methodology ofExample 61. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.15 g of2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)pyridine (Yield=75%). ¹HNMR (500 MHz, CD₃OD): δ 8.12 (d, J=5.0 Hz, 1H), 7.68 (t, J=9.5 Hz, 1H),7.27 (t, J=6.5 Hz, 2H), 7.07-6.94 (m, 4H), 6.82 (d, J=8.0 Hz, 1H), 4.47(t, J=7.0 Hz, 2H), 2.91 (t, J=5.5 Hz, 2H), 2.79 (bs, 4H), 2.03 (t,J=13.5 Hz, 2H), 1.78-1.73 (m, 2H), 1.29 (s, 3H); ESI+MS: m/z 313([M+H]⁺).

Example-175: 4-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)-1H-indole

Title compound was prepared from 4-methyl-4-phenoxypiperidinehydrochloride (0.075 g, 0.33 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (3%MeOH/CH₂Cl₂ as eluent) afforded 0.06 g of4-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)-1H-indole (Yield=51%). ¹HNMR (400 MHz, DMSO-d₆): δ 11.06 (s, 1H), 7.28 (t, J=15.5 Hz, 2H), 7.21(s, 1H), 7.07-6.96 (m, 5H), 6.50 (d, J=6.0 Hz, 1H), 6.40 (s, 1H), 4.20(s, 2H), 2.89-2.64 (m, 6H), 1.89 (bs, 2H), 1.66 (bs, 2H), 1.25 (s, 3H);ESI+MS: m/z 351 ([M+H]⁺).

Example-176:4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol

1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-one

Title compound was prepared from piperidin-4-one hydrochloride (2.0 g,13.0 mmol) using the general methodology of Example-1. Purificationusing silica gel column chromatography (30% EA/Hexanes as eluent)afforded 2.5 g of 1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-one(Yield=67%).

4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol

To a stirred solution of1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-one (200 mg, 0.70mmol) in dry THF (5 mL) under argon atmosphere was added isopropylmagnesium chloride (2M in THF, 1 mL, 2.0 mmol) at 0° C. The reactionmixture was warmed to RT and stirred for 2 h. After completion of thereaction (monitored by TLC), the mixture was quenched with NH₄Clsolution at 0° C. and extracted with EtOAc. The combined organic layerswas dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.The crude compound was purified by column preparative HPLC and afforded10 mg of4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol ascolorless syrup (Yield=5%). ¹H NMR (400 MHz, CD₃OD): δ 7.58-7.54 (m,2H), 7.18 (d, J=8.8 Hz, 1H), 7.08-7.04 (m, 1H), 4.28 (t, J=5.6 Hz, 2H),2.98-2.91 (m, 4H), 2.69-2.63 (m, 2H), 1.74-1.66 (m, 2H), 1.63-1.54 (m,3H), 0.92 (d, J=6.8 Hz, 6H); ESI+MS: m/z 332 ([M+H]⁺).

Example-177:4-methyl-1′-(2-(trifluoromethyl)phenyl)-[1,3′-bipiperidin]-4-ol

tert-butyl 4-hydroxy-4-methyl-[1,3′-bipiperidine]-1′-carboxylate

To a stirred solution of 4-methylpiperidin-4-ol hydrochloride (100 mg,0.66 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (131 mg, 0.66mmol) in DCM (2 mL) were added NaBH(OAc)₃ (210 mg, 0.99 mmol) followedby acetic acid (0.038 mL, 0.66 mmol) at 0° C. The reaction mixture wasstirred at RT for 16 h. After completion (monitored by TLC), thereaction was diluted with sat. aq. NaHCO₃ and extracted with DCM. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude material was purified by silica gel columnchromatography (gradient of MeOH in DCM) and afforded 0.05 g oftert-butyl 4-hydroxy-4-methyl-[1,3′-bipiperidine]-1′-carboxylate(Yield=25%).

4-methyl-[1,3′-bipiperidin]-4-ol hydrochloride

Title compound was prepared from tert-butyl4-hydroxy-4-methyl-[1,3′-bipiperidine]-1′-carboxylate (50 mg, 0.17 mmol)using the general methodology of step 2 of key intermediate-VI andafforded 40 mg of 4-methyl-[1,3′-bipiperidin]-4-ol hydrochloride(Yield=quant.).

4-methyl-1′-(2-(trifluoromethyl)phenyl)-[1,3′-bipiperidin]-4-ol

To a stirred solution of 4-methyl-[1,3′-bipiperidin]-4-ol hydrochloride(40 mg, 0.17 mmol) and 1-bromo-2-(trifluoromethyl)benzene (38 mg, 0.17mmol) in toluene (2 mL) was added Cs₂CO₃ (167 mg, 0.51 mmol) and(+/−)-BINAP (11 mg, 0.017 mmol) at room temperature. The reactionmixture was degased with argon for 10 min then Pd₂(dba)₃ (16 mg, 0.017mmol) was added and the reaction mixture was heated at 100° C. in asealed tube for 16 h. After completion of the reaction (monitored byTLC), the mixture was diluted with water and extracted with DCM. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude residue was purified by preparative HPLC toafford 20 mg of4-methyl-1′-(2-(trifluoromethyl)phenyl)-[1,3′-bipiperidin]-4-ol as athick syrup (Yield=35%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.62 (t, J=7.6 Hz,2H), 7.51 (d, J=8.0 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 4.00 (brs, 1H),3.18-3.05 (m, 1H), 2.85 (d, J=10.0 Hz, 1H), 2.65-2.40 (m, 7H), 1.87 (d,J=10.6 Hz, 1H), 1.76 (d, J=12.4 Hz, 1H), 1.58-1.51 (m, 1H), 1.41-1.31(m, 5H), 1.05 (s, 3H); ESI+MS: m/z 343 ([M+H]⁺).

Example-178:1-(4-chlorophenyl)-8-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-1,8-diazaspiro[4.5]decane

Title compound was prepared from1-(4-chlorophenyl)-1,8-diazaspiro[4.5]decane hydrochloride (0.04 g, 0.14mmol) using the general methodology of Example-1. Purification usingsilica gel column chromatography (5% MeOH/CH₂Cl₂ as eluent) afforded0.025 g of1-(4-chlorophenyl)-8-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-1,8-diazaspiro[4.5]decane(Yield=45%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.19-7.15 (m, 2H), 6.87-6.81(m, 4H), 6.81-6.74 (m, 2H), 4.37-4.31 (m, 2H), 4.01-3.96 (m, 1H), 3.24(t, J=6.4 Hz, 2H), 2.99-2.96 (m, 1H), 2.89-2.86 (m, 1H), 2.59 (d, J=5.6Hz, 2H), 2.45-2.44 (m, 1H), 2.26-2.12 (m, 2H), 1.96-1.94 (m, 2H),1.88-1.81 (m, 2H), 1.25-1.20 (m, 3H); ESI+MS: m/z 399 ([M+H]⁺). Theenantiomers of 178 were separated using chiral HPLC (method U) andafforded the pure enantiomers 178a and 178b.

Example-179:1′-(2-(2-(trifluoromethyl)phenoxy)ethyl)-3H-spiro[benzofuran-2,4′-piperidine]

tert-butyl 4-(2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate

Magnesium turnings (220 mg, 9.0 mmol) and a crystal of iodine weredissolved in diethyl ether (5 ml). The resulting mixture was warmed to35° C. When color disappeared, 2-(bromomethyl)-4-chloro-1-fluorobenzene(0.91 mL, 7.53 mmol) in diethyl ether (3 mL) was added dropwise over 30minutes. The reaction mixture was kept at 35° C. overnight. A solutionof tert-butyl 4-oxopiperidine-1-carboxylate (1.0 g, 5.0 mmol) in 5 ml ofdiethyl ether was then added dropwise over 15 minutes. Stirring wascontinued for 1 h at RT. The reaction mixture was then extracted withethyl acetate/aq.NH₄Cl. The combined organic layer was dried overNa₂SO₄, filtered and concentrated. Purification using silica gel columnchromatography (gradient EA/Hexanes as eluent) afforded 900 mg oftert-butyl 4-(2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate(Yield=58%).

tert-butyl 3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate

tert-Butyl 4-(2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate (900 mg,2.9 mmol) was dissolved in a DMF/Toluene solution (1/1, 14 mL) underargon. NaH (198 mg, 4.95 mmol) was added in 1 portion and the mixturewas stirred at 90° C. After 20 h, the mixture was extracted with ethylacetate/aq.NH₄Cl. The combined organic layer was dried over Na₂SO₄,filtered and concentrated. Purification using silica gel columnchromatography (gradient MeOH/DCM as eluent) afforded 580 mg oftert-butyl 3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate(Yield=69%).

3H-spiro[benzofuran-2,4′-piperidine]

tert-butyl 3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate (580 mg,2.0 mmol) was dissolved in DCM (2 mL) and TFA (1.5 mL, 20.0 mmol) wasadded dropwise. After 3 h at room temperature, solvents were evaporated,the mixture was dissolved in DCM and washed with aq.NaHCO₃. The organiclayer was dried over Na₂SO₄, filtered and concentrated to afford 350 mgof 3H-spiro[benzofuran-2,4′-piperidine] (Yield=92%).

1′-(2-(2-(trifluoromethyl)phenoxy)ethyl)-3H-spiro[benzofuran-2,4′-piperidine]

Title compound was prepared from 3H-spiro[benzofuran-2,4′-piperidine](0.05 g, 0.26 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (3% MeOH/CH₂Cl₂ aseluent) afforded 0.06 g of 1′-(2-(2-(trifluoromethyl)phenoxy)ethyl)-3H-spiro[benzofuran-2,4′-piperidine] (Yield=60%). ¹H NMR(300 MHz, CDCl₃): δ 7.56 (d, J=7.5 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H),7.16-7.05 (m, 2H), 7.03-6.95 (m, 2H), 6.85-6.72 (m, 2H), 4.21 (t, J=5.7Hz, 2H), 2.99 (s, 2H), 2.92 (t, J=5.6 Hz, 2H), 2.85-2.60 (m, 4H),2.05-1.90 (m, 2H), 1.88-1.75 (m, 2H); ESI+MS: m/z 378 ([M+H]⁺).

One of skill in the art would understand the present invention toencompass subgenera that may be derived from the foregoing genera,subgenera and list of exemplary compounds, as herein disclosed or hereinlisted. Further, from the foregoing and the disclosure herein, theskilled person can readily select suitable moieties for any of thevariable substituents identified in the formulae herein described.

Example-180:3-(4-chlorophenoxy)-1-(2-(3-fluorophenoxy)ethyl)-3-methylpyrrolidine

Title compound was prepared from 3-(4-chlorophenoxy)-3-methylpyrrolidinehydrochloride (0.10 g) and 1-(2-bromoethoxy)-2-fluorobenzene (0.14 g,0.63 mmol, 1.2 equiv) using the general methodology of Example-1. Thecrude was purified by preparative HPLC purification to afford 0.09 g of3-(4-chlorophenoxy)-1-(2-(3-fluorophenoxy)ethyl)-3-methylpyrrolidine(Yield=54%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.33-7.24 (m, 3H), 6.99-6.95(m, 2H), 6.87-6.72 (m, 3H), 4.08 (t, J=11.6 Hz, 2H), 3.00 (d, J=10.0 Hz,1H), 2.86-2.76 (m, 3H), 2.72-2.60 (m, 2H), 2.22-2.15 (m, 1H), 1.96-1.89(m, 1H), 1.45 (s, 3H); ESI+MS: m/z 350 ([M+H]⁺).

Example-181: 1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine]

3-(2-fluorobenzyl)-1-(2-phenoxyethyl)pyrrolidin-3-ol (Compound 300)

Title compound was prepared from 1-(2-phenoxyethyl)pyrrolidin-3-one(0.25 g, 1.22 mmol) and 1-(bromomethyl)-2-fluorobenzene (0.35 g, 1.83mmol) using the methodology of step 1 of Example-179. The crude waspurified by silica gel chromatography to afford 0.13 g of3-(2-fluorobenzyl)-1-(2-phenoxyethyl)pyrrolidin-3-ol (Yield=33%).ESI+MS: m/z 316.3 ([M+H]⁺).

1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine]

Title compound was prepared from3-(2-fluorobenzyl)-1-(2-phenoxyethyl)pyrrolidin-3-ol (0.12 g, 0.38 mmol)using the methodology of step 2 of Example-179. The crude was purifiedby silica gel chromatography to afford 0.054 g of1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine] (Yield=48%).¹H NMR (400 MHz, CDCl₃): δ 7.33-7.26 (m, 2H), 7.16-7.07 (m, 2H),6.97-6.75 (m, 5H), 4.12 (t, J=5.9 Hz, 2H), 3.30-3.10 (m, 3H), 3.10-3.00(m, 1H), 2.96 (t, J=5.9 Hz, 2H), 2.80-2.72 (m, 2H), 2.43-2.32 (m, 1H),2.10-1.98 (m, 1H); ESI+MS: m/z 296.3 ([M+H]⁺).

Example-182:3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)pyridine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.1 g, 0.38 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.025 g of3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)pyridine(Yield=19%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (d, J=2.4 Hz, 1H), 8.16(d, J=4.2 Hz, 1H), 7.42-7.37 (m, 1H), 7.31 (d, J=8.8 Hz, 3H), 7.01 (d,J=8.7 Hz, 2H), 4.17-4.13 (m, 2H), 2.77-2.70 (m, 2H), 2.60-2.53 (m, 4H),1.89-1.82 (m, 2H), 1.66-1.59 (m, 2H), 1.24 (s, 3H); ESI+MS: m/z 347([M+H]⁺).

Example-183:4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)pyridine

2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethan-1-ol

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.5 g, 1.91 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (10%MeOH/CH₂Cl₂ as eluent) afforded 0.35 g of2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethan-1-ol (Yield=68%).ESI+MS: m/z 270.0 ([M+H]⁺).

4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)pyridine

Title compound was prepared from2-(4-methyl-4-phenoxypiperidin-1-yl)ethanol (0.05 g, 0.19 mmol) and4-bromopyridine (43 mg, 0.22 mmol) using the general methodology ofExample 61. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.025 g of4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)pyridine(Yield=39%). ¹H NMR (500 MHz, CD₃OD): δ 8.38-8.34 (m, 2H), 7.31 (d,J=8.8 Hz, 2H), 7.01 (d, J=8.9 Hz, 2H), 6.98-6.95 (m, 2H), 4.16 (t, J=5.8Hz, 2H), 2.73 (t, J=5.7 Hz, 2H), 2.60-2.54 (m, 4H), 1.89-1.82 (m, 2H),1.67-1.58 (m, 2H), 1.24 (s, 3H); ESI+MS: m/z 346.9 ([M+H]⁺).

Example-184:5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)phenol

4-(4-chlorophenoxy)-1-(2-(3-((4-methoxybenzyl)oxy)-4-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from2-(4-methyl-4-phenoxypiperidin-1-yl)ethanol (0.30 g, 1.11 mmol) and4-fluoro-2-((4-methoxybenzyl)oxy)-1-(trifluoromethyl)benzene (334 mg,1.11 mmol) using the general methodology of Example 61. Purificationusing silica gel column chromatography (5% MeOH/CH₂Cl₂ as eluent)afforded 0.4 g of4-(4-chlorophenoxy)-1-(2-(3-((4-methoxybenzyl)oxy)-4-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine(Yield=65%). ESI+MS: m/z 550.4 ([M+H]⁺).

5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)phenol

4-(4-chlorophenoxy)-1-(2-(3-((4-methoxybenzyl)oxy)-4-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine(0.25 g, 0.46 mmol) was dissolved in DCM (5 mL) and the mixture wascooled to 0° C. trifluoroacetic acid (0.175 mL, 2.27 mmol) was addeddropwise and the mixture was stirred at room temperature overnight. Thereaction mixture was then diluted in saturated aqueous NaHCO₃ andextracted with DCM. The organic layers were dried over Na₂SO₄, filteredand concentrated. Purification using silica gel column chromatography(2% MeOH/CH₂Cl₂ as eluent) afforded 0.04 g of5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)phenol(Yield=21%). ¹H NMR (500 MHz, CD₃OD): δ 10.46 (bs, 1H), 7.38 (d, J=8.4Hz, 1H), 7.33-7.29 (m, 2H), 7.02-6.98 (m, 2H), 6.52-6.47 (m, 2H), 4.06(t, J=6.0 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 2.56-2.53 (m, 4H), 1.88-1.83(m, 2H), 1.65-1.58 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 430.4 ([M+H]⁺).

Example-185:4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)benzonitrile

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.07 g, 0.27 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (5%MeOH/CH₂Cl₂ as eluent) afforded 0.06 g of4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)benzonitrile(Yield=61%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.75 (d, J=8.5 Hz, 2H), 7.31(d, J=9.0 Hz, 2H), 7.11 (d, J=9.0 Hz, 2H), 7.00 (d, J=8.5 Hz, 2H), 4.17(t, J=5.5 Hz, 2H), 2.73 (t, J=5.5 Hz, 2H), 2.60-2.55 (m, 4H), 1.86-1.83(m, 2H), 1.64-1.58 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 371.0 ([M+H]⁺).

Example-186:1-(2-((1H-pyrazol-4-yl)oxy)ethyl)-4-(4-chlorophenoxy)-4-methylpiperidine

tert-butyl4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-1H-pyrazole-1-carboxylate

Title compound was prepared from2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl methanesulfonate(0.1 g, 0.29 mmol) using the general methodology of Example-1.Purification using silica gel column chromatography (2% MeOH/CH₂Cl₂ aseluent) afforded 0.05 g of tert-butyl4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-1H-pyrazole-1-carboxylate(Yield=40%). ESI+MS: m/z 436.1 ([M+H]⁺).

1-(2-((1H-pyrazol-4-yl)oxy)ethyl)-4-(4-chlorophenoxy)-4-methylpiperidine

To a stirred solution of tert-butyl4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-1H-pyrazole-1-carboxylate(0.05 g, 0.12 mmol) in DCM (5 mL), was added TFA (0.044 mL, 0.57 mmol)at 0° C. The reaction mixture was stirred at RT for 2 h. The solvent wasremoved under reduced pressure. Purification using silica gel columnchromatography (10% MeOH/CH₂Cl₂ as eluent) afforded 0.015 g of1-(2-((1H-pyrazol-4-yl)oxy)ethyl)-4-(4-chlorophenoxy)-4-methylpiperidine(Yield=39%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.31 (br s, 1H), 7.43 (br s,1H), 7.31 (d, J=8.8 Hz, 2H), 7.23 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H),3.92 (t, J=5.8 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.53-2.50 (m, 4H),1.88-1.82 (m, 2H), 1.66-1.57 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z 336.0([M+H]⁺).

Example-187:1-(2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-5-fluorophenyl)ethan-1-one

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.1 g, 0.38 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.06 g of1-(2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-5-fluorophenyl)ethan-1-one(Yield=39%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.42-7.35 (m, 1H), 7.34-7.29(m, 3H), 7.23 (dd, J=9.1 Hz, J=4.3 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.19(t, J=5.6 Hz, 2H), 2.76 (t, J=5.1 Hz, 2H), 2.59 (s, 3H), 2.57-2.53 (m,4H), 1.89-1.82 (m, 2H), 1.64-1.56 (m, 2H), 1.24 (s, 3H); ESI+MS: m/z406.0 ([M+H]⁺).

Example-188:4-(4-chlorophenoxy)-1-(2-(2-methoxyphenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.1 g, 0.38 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.11 g of4-(4-chlorophenoxy)-1-(2-(2-methoxyphenoxy)ethyl)-4-methylpiperidine(Yield=77%). ¹H NMR (500 MHz, CD₃OD): δ 7.27 (d, J=8.5 Hz, 2H),7.03-6.88 (m, 6H), 4.19 (t, J=5.5 Hz, 2H), 3.83 (s, 3H), 3.03-2.83 (m,6H), 2.05 (t, J=13.5 Hz, 2H), 1.83-1.76 (m, 2H), 1.30 (s, 3H); ESI+MS:m/z 376.1 ([M+H]⁺).

Example-189:4-(4-chlorophenoxy)-1-(2-(4,5-difluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.07 g, 0.27 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.03 g of4-(4-chlorophenoxy)-1-(2-(4,5-difluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine(Yield=27%). ¹H NMR (500 MHz, CD₃OD): δ 7.25 (d, J=8.0 Hz, 2H),7.01-6.92 (m, 4H), 4.14 (t, J=5.5 Hz, 2H), 3.80 (s, 3H), 2.93 (t, J=5.5Hz, 2H), 2.85-2.80 (m, 4H), 2.06-1.99 (m, 2H), 1.80-1.72 (m, 2H), 1.29(s, 3H); ESI+MS: m/z 412.1 ([M+H]⁺).

Example-190:4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-isopropoxyphenoxy)ethyl)-4-methylpiperidine

2-(allyloxy)-4-fluorophenol

Title compound was prepared from 4-fluorobenzene-1,2-diol (2.0 g, 15.61mmol) using the general methodology of Int-3. Purification using silicagel column chromatography afforded 1.2 g of 2-(allyloxy)-4-fluorophenol(Yield=46%). ESI+MS: m/z 167.0 ([M−H]⁻).

2-(allyloxy)-4-fluoro-1-isopropoxybenzene

Title compound was prepared from 2-(allyloxy)-4-fluorophenol (2.0 g,15.61 mmol) using the general methodology of Int-3. Purification usingsilica gel column chromatography afforded 0.4 g of2-(allyloxy)-4-fluoro-1-isopropoxybenzene (Yield=64%).

2-(5-fluoro-2-isopropoxyphenoxy)acetaldehyde

To a stirred solution of 2-(allyloxy)-4-fluoro-1-isopropoxybenzene (0.4g, 1.9 mmol) in acetone: water (3:2) was added potassium osmium (VI)oxide dihydrate (0.025 g, 0.067 mmol) and NaIO₄ (1.63 g, 7.61 mmol) at0° C. The reaction mixture was stirred at room temperature for 4 h. Thereaction mass was filtered and concentrated under reduced pressure. Thenwater was added and extracted with EtOAc. The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure and afforded 0.3 g of2-(5-fluoro-2-isopropoxyphenoxy)acetaldehyde (Yield=74%). ESI+MS: m/z213.3 ([M+H]⁺).

4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-isopropoxyphenoxy)ethyl)-4-methylpiperidine

To a stirred solution of 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.37 g, 1.41 mmol) and2-(5-fluoro-2-isopropoxyphenoxy)acetaldehyde (0.3 g, 1.41 mmol) in DCM(10 mL) were added NaBH(OAc)₃ (0.897 g, 4.23 mmol) and AcOH (0.08 mL,1.41 mmol) at 0° C. The reaction mixture was stirred at room temperaturefor 16 h. After completion, the reaction was diluted with DCM. Theorganic layer was washed with water, brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. Purification using silica gelcolumn chromatography followed by preparative HPLC afforded 0.05 g of4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-isopropoxyphenoxy)ethyl)-4-methylpiperidine(Yield=9%). ¹H NMR (400 MHz, CD₃OD): δ 7.28-7.22 (m, 2H), 7.02-6.96 (m,2H), 6.91 (dd, J=8.9, 5.7 Hz, 1H), 6.80 (dd, J=10.3, 3.0 Hz, 1H),6.63-6.57 (m, 1H), 4.46-4.38 (m, 1H), 4.16 (t, J=5.5 Hz, 2H), 2.90 (t,J=5.5 Hz, 2H), 2.83-2.73 (m, 4H), 2.05-1.97 (m, 2H), 1.78-1.69 (m, 2H),1.29 (s, 3H), 1.26 (d, J=6.0 Hz, 6H); ESI+MS: m/z 422.4 ([M+H]⁺).

Example-191:4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-isopropoxyphenoxy)ethyl)-4-methylpiperidine

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.07 g, 0.27 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.025 g of4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-isopropoxyphenoxy)ethyl)-4-methylpiperidine(Yield=16%). ¹H NMR (400 MHz, CD₃OD): δ 7.28-7.22 (m, 2H), 6.99 (d,J=9.0 Hz, 2H), 6.95 (dd, J=8.9, 5.6 Hz, 1H), 6.75 (dd, J=10.5, 2.9 Hz,1H), 6.63-6.57 (m, 1H), 4.59-4.51 (m, 1H), 4.13 (t, J=5.5 Hz, 2H), 2.86(t, J=5.5 Hz, 2H), 2.82-2.72 (m, 4H), 2.04-1.98 (m, 2H), 1.80-1.70 (m,2H), 1.31 (s, 3H), 1.29 (s, 6H); ESI+MS: m/z 422.0 ([M+H]⁺).

Example-192:4-(4-chlorophenoxy)-4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

4-(prop-1-en-2-yl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol

To a stirred solution of1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-one (0.5 g, 1.74mmol) in THF (5 mL) was added dropwise isopropenyl magnesium bromide(0.5M in THF, 5.2 mL, 2.61 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 2 h. The reaction was quenched with aq.NH₄Cl andextracted with EtOAc. The organic layer was separated, dried overNa₂SO₄, filtered and concentrated. Purification by silica gelchromatography, eluting with 5% MeOH, afforded 0.25 g of4-(prop-1-en-2-yl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(Yield=44%). ESI+MS: m/z 329.9 ([M+H]⁺).

4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol

To a stirred solution of4-(prop-1-en-2-yl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(0.25 g, 0.76 mmol) in ethanol (5 mL) was added 10% Pd/C (0.025 g, 0.23mmol). The reaction mixture was stirred at room temperature underhydrogenation balloon pressure for 5 h. After completion, the reactionwas filtered through a pad of celite and washed with MeOH. The filtratewas concentrated under reduced pressure to afford 0.2 g of4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(Yield=80%). ESI+MS: m/z 332.3 ([M+H]⁺).

4-(4-chlorophenoxy)-4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

Title compound was prepared from4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol (0.2g, 0.60 mmol) using the general methodology of Example-61. Purificationusing silica gel column chromatography afforded 9 mg of4-(4-chlorophenoxy)-4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=4%). ¹H NMR (400 MHz, CD₃OD): δ 7.59-7.53 (m, 2H), 7.23-7.19 (m,2H), 7.17 (d, J=8.4 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 7.00-6.96 (m, 2H),4.24 (t, J=5.6 Hz, 2H), 2.91-2.81 (m, 4H), 2.67-2.55 (m, 2H), 2.35-2.27(m, 1H), 1.94-1.82 (m, 4H), 0.99 (d, J=6.8 Hz, 6H); ESI+MS: m/z 441.9([M+H]⁺).

Example-193:4-(4-chlorophenoxy)-4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

tert-butyl 4-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylate

To a stirred solution of ethynyltrimethylsilane (5.92 g, 60.2 mmol) inTHF (50 mL) was added n-BuLi (1.6 M in hexane, 3.8 mL, 60.2 mmol)dropwise at −40° C. The reaction mixture was stirred at −40° C. for 1 h.To the mixture was added a solution of tert-butyl4-oxopiperidine-1-carboxylate (10.0 g, 50.2 mmol) in THF (50 mL)dropwise at −60° C. After stirring at −60° C. for 30 min, the reactionmixture was allowed to warm to room temperature and was stirred for 16h. The reaction was quenched with sat.NH₄Cl and extracted with ethylacetate. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. Purification by silica gel chromatography (eluent 10%ethyl acetate in hexanes) afforded 6.0 g of tert-butyl4-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylate(Yield=41%).

4-((trimethylsilyl)ethynyl)piperidin-4-ol

Title compound was prepared from tert-butyl4-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylate (5.0 g,16.8 mmol) using the general methodology of step 2 of keyintermediate-VI and afforded 3.5 g of4-((trimethylsilyl)ethynyl)piperidin-4-ol (Yield=89%).

4-ethynylpiperidin-4-ol

To a stirred solution of 4-((trimethylsilyl)ethynyl)piperidin-4-olhydrochloride (3.3 g, 14.1 mmol) in MeOH (5 mL) was added K₂CO₃ (5.85 g,42.3 mmol). The reaction mixture was maintained at room temperature for16 h. Solvent was evaporated and the mixture was diluted with water andextracted with DCM. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated to afford 1.3 g of 4-ethynylpiperidin-4-ol(Yield=74%).

4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(Compound 302)

To a stirred solution of 4-ethynylpiperidin-4-ol (1.2 g, 9.6 mmol) inacetonitrile (30 mL) was added K₂CO₃ (3.97 g, 28.8 mmol) and1-(2-bromoethoxy)-2-(trifluoromethyl)benzene (2.6 g, 9.6 mmol) at roomtemperature. The reaction mixture was heated at 80° C. for 16 h. Thereaction mixture was diluted with water and extracted with DCM. Theorganic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. Purification by silica gel chromatography (eluent 2% MeOHin DCM) afforded 2.5 g of4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol(Yield=83%). ESI+MS: m/z 314.0 ([M+H]⁺).

4-ethynyl-4-(4-nitrophenoxy)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

To a stirred solution of4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol (1.5 g,4.79 mmol) in DMA (10 mL) was added NaH (0.17 g, 7.2 mmol) at 0° C. Thereaction mixture was stirred at 50° C. for 1 h. Then1-fluoro-4-nitrobenzene (1.0 g, 7.2 mmol) was added and the reactionmixture was heated at 80° C. for 16 h. The reaction was diluted withwater and extracted with ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. Purification by silica gelchromatography (eluent 2% MeOH in DCM) afforded 1.3 g of4-ethynyl-4-(4-nitrophenoxy)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=63%). ESI+MS: m/z 435.1 ([M+H]⁺).

4-((4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)aniline

To a stirred solution of4-ethynyl-4-(4-nitrophenoxy)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(1.2 g, 2.76 mmol) in EtOH:H₂O (1:1, 10 mL) was added Iron (0.23 g, 4.14mmol) followed by NH₄Cl (0.22 g, 4.14 mmol). The reaction mixture washeated at 80° C. for 5 h. The reaction mixture was filtered through apad of celite, and the filtrate was concentrated under reduced pressureand diluted with sat.NaHCO₃ solution. The aqueous layer was extractedwith ethyl acetate, dried over anhydrous Na₂SO₄, filtered andconcentrated. Purification by silica gel chromatography (eluent with 50%ethyl acetate in hexanes) afford 1.0 g of4-((4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)aniline(Yield=90%). ESI+MS: m/z 405.1 ([M+H]⁺).

4-(4-chlorophenoxy)-4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

To a stirred solution of4-((4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)aniline(0.1 g, 0.25 mmol) in DMF (4 mL) was added isoamyl nitrite (0.05 mL,0.37 mmol) dropwise. The reaction mixture was stirred at roomtemperature for 15 min. Then CuCl₂ (0.05 g, 0.37 mmol) was added and themixture was stirred for 4 h. The reaction was quenched with a solutionof sat.NaHCO₃ and extracted with ethyl acetate. The organic layer wasseparated, dried over anhydrous Na₂SO₄ and concentrated. Purification byPreparative HPLC afforded 8 mg of4-(4-chlorophenoxy)-4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=8%). ¹H NMR (400 MHz, CD₃OD): δ 7.58-7.51 (m, 2H), 7.26-7.15 (m,5H), 7.04 (t, J=7.6 Hz, 1H), 4.24 (t, J=5.4 Hz, 2H), 3.19 (s, 1H),2.92-2.84 (m, 4H), 2.72-2.65 (m, 2H), 2.07 (t, J=5.5 Hz, 4H); ESI+MS:m/z 424.0 ([M+H]⁺).

Example-194:4-ethynyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

To a stirred solution of4-((4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)aniline(0.1 g, 0.25 mmol) in 37% HCl:H₂O (1:1, 1 mL) was added sodium nitrite(0.022 g, 0.32 mmol) at 0° C. The reaction mixture was stirred at 0° C.for 1 h. The reaction mixture was added to a solution of CuCl (0.04 g,0.40 mmol) in 37% HCl:H₂O (1:1, 1 mL) at 0° C. The reaction mixture wasstirred at room temperature for 16 h. The reaction was basified with asolution of 50% NaOH and extracted with ethyl acetate. The organic layerwas separated, dried over anhydrous Na₂SO₄ and concentrated.Purification by Preparative HPLC afforded 15 mg of4-ethynyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(Yield=16%). ¹H NMR (400 MHz, CD₃OD): δ 7.59-7.52 (m, 2H), 7.29-7.15 (m,5H), 7.08-6.98 (m, 2H), 4.25 (t, J=5.5 Hz, 2H), 3.15 (s, 1H), 2.93-2.84(m, 4H), 2.73-2.65 (m, 2H), 2.09 (br t, J=5.4 Hz, 4H); ESI+MS: m/z 390.4([M+H]⁺).

Example-195:1-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one

Title compound was prepared from 4-(4-chlorophenoxy)-4-methylpiperidinehydrochloride (0.05 g, 0.19 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.018 g of1-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one(Yield=23%). ¹H NMR (400 MHz, CD₃OD): δ 7.97 (d, J=6.8 Hz, 1H), 7.90 (d,J=6.6 Hz, 1H), 7.30 (d, J=9.6 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 6.35 (t,J=6.8 Hz, 1H), 4.06 (t, J=6.0 Hz, 2H), 2.65-2.57 (m, 2H), 2.57-2.53 (m,4H), 1.86-1.78 (m, 2H), 1.63-1.52 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z415.3 ([M+H]⁺).

Example-196: (1R,3 s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol

tert-butyl(1R,3s,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-oxirane]-8-carboxylate

To a solution of (1R,5S)-tert-butyl3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate (8.9 g, 39.9 mmol)in DCM (133 mL) was added m-CPBA portionwise (14.3 g, 63.8 mmol) and thesolution was stirred at room temperature for 15 h. The reaction mixturewas diluted in sat. aq. NaHCO₃ and extracted with DCM. The 2stereoisomers were separated by flash chromatography (Hexane/EtOAc 95:5)and afforded 2.6 g of tert-butyl(1R,3s,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-oxirane]-8-carboxylate(Yield=27%). ¹H NMR (400 MHz, CDCl₃): δ 4.45-4.25 (m, 2H), 2.76 (s, 2H),2.35-2.10 (m, 2H), 2.10-1.90 (m, 2H), 1.80-1.60 (m, 2H), 1.50 (s, 9H),1.30-1.20 (m, 2H).

tert-butyl(1R,3s,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate

To a stirred solution of tert-butyl(1R,3s,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,2′-oxirane]-8-carboxylate(2.6 g, 10.9 mmol) in THF (50 mL) was added LiBHEt₃ (1.0 M in THF, 12mL, 12 mmol) at 0° C. The reaction mass was stirred at 0° C. for 2 h.The reaction mixture was diluted with sat. NH₄Cl solution and extractedwith ethyl acetate. The organic layer was separated, dried overanhydrous Na₂SO₄, filtered and concentrated. Purification by flashchromatography (Hexane/EtOAc 70:30) afforded 1.6 g of tert-butyl(1R,3s,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate(Yield=61%). ¹H NMR (400 MHz, DMSO-d₆): δ 4.41 (s, 1H), 4.05-3.95 (m,2H), 1.90-1.75 (m, 4H), 1.70-1.60 (m, 4H), 1.40 (s, 9H), 1.34 (s, 3H).ESI+MS: m/z 242.0 ([M+H]⁺).

(1R,3s,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octan-8-ium2,2,2-trifluoroacetate

tert-butyl(1R,3s,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate(200 mg, 0.83 mmol) was dissolved in Toluene (3 ml) and TFA (0.5 ml) wasadded dropwise. The reaction mixture was stirred for 1 hour and thesolvents were evaporated and coevaporated again with fresh toluene toafford 210 mg of(1R,3s,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octan-8-ium2,2,2-trifluoroacetate (Yield=quant.).

(1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol

Title compound was prepared from(1R,3s,5S)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octan-8-ium2,2,2-trifluoroacetate (0.25 g, 0.98 mmol) using the general methodologyof Example-1. Purification using silica gel column chromatographyafforded 0.11 g of(1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol(Yield=34%). ¹H NMR (400 MHz, CD₃OD): δ 7.97 (d, J=6.8 Hz, 1H), 7.90 (d,J=6.6 Hz, 1H), 7.30 (d, J=9.6 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 6.35 (t,J=6.8 Hz, 1H), 4.06 (t, J=6.0 Hz, 2H), 2.65-2.57 (m, 2H), 2.57-2.53 (m,4H), 1.86-1.78 (m, 2H), 1.63-1.52 (m, 2H), 1.23 (s, 3H); ESI+MS: m/z415.3 ([M+H]⁺).

Example-197: (1R,3 s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol

(1R,3s,5S)-3-methyl-3-(4-nitrophenoxy)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octane

To a suspension of(1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol(0.1 g, 0.3 mmol) in dry DMF (1 mL), was added NaH (24 mg, 0.61 mmol).The mixture was stirred at 80° C. for 1 h and then cooled to −70° C. Asolution of 1-fluoro-4-nitrobenzene (55 uL, 0.52 mmol) in dry DMF (0.5ml) was added dropwise. The reaction was left to warm up to roomtemperature and left stirring overnight. The mixture was poured in waterand extracted with EtOAc, the organic phase washed with water, dried(Na₂SO₄), filtered and concentrated. Purification by silica gelchromatography (DCM/MeOH 99:1) afforded 76 mg of (1R,3s,5S)-3-methyl-3-(4-nitrophenoxy)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octane(Yield=56%).

4-(((1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)aniline

To a stirred solution of(1R,3s,5S)-3-methyl-3-(4-nitrophenoxy)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octane(0.07 g, 0.16 mmol) in MeOH (0.8 mL) was added 10% Pd/C (10 mg) at roomtemperature and the reaction was stirred for 16 h under H₂ balloonatmosphere. After completion, the reaction mass was filtered through apad of celite and the filtrate was concentrated. Purification by silicagel chromatography afforded 0.035 g of4-(((1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)aniline(Yield=54%).

(1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol

Title compound was prepared from4-(((1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)aniline(0.035 g, 0.08 mmol) using the general methodology of Key intermediateVI and afforded 0.016 g of(1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol(Yield=46%). ¹H NMR (400 MHz, CDCl₃): δ 7.58-7.55 (m, 1H), 7.53-7.45 (m,1H), 7.25-7.18 (m, 2H), 7.06-6.97 (m, 5H), 4.27 (t, J=5.6 Hz, 2H), 3.56(br s, 2H), 3.07-3.01 (m, 2H), 2.62-2.52 (m, 2H), 2.10-2.00 (m, 2H),1.80-1.70 (m, 4H), 1.26 (s, 3H); ESI+MS: m/z 407.5 ([M+H]⁺).

Example-198:N,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxamide

tert-butyl 4-methyl-4-(methylcarbamoyl)piperidine-1-carboxylate

To a stirred solution of1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (1.0 g,4.11 mmol) in DMF (10 mL) was added methyl amine hydrochloride (0.36 g,5.34 mmol), HATU (2.34 g, 6.2 mmol) followed by DIPEA (2.66 g, 20.55mmol) at 0° C. The reaction mixture was stirred at room temperature for16 h. After completion, the mixture was quenched with water andextracted with diethyl ether. The organic layer was separated, driedover Na₂SO₄, filtered and concentrated. Purification by silica gelchromatography eluting with 3% MeOH in DCM afforded 0.8 g of tert-butyl4-methyl-4-(methylcarbamoyl)piperidine-1-carboxylate (Yield=76%).

N,4-dimethylpiperidine-4-carboxamide hydrochloride

To a stirred solution of tert-butyl4-methyl-4-(methylcarbamoyl)piperidine-1-carboxylate (0.6 g, 2.34 mmol)in DCM (5 mL) was added 4.0M HCl in 1,4-Dioxane (0.7 mL, 28.0 mmol) at0° C. The reaction mixture was stirred at room temperature for 4 h.After completion, volatiles were concentrated under reduced pressure toafford 0.45 g of N,4-dimethylpiperidine-4-carboxamide hydrochloride(Yield=quant.).

N,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxamide

Title compound was prepared from N,4-dimethylpiperidine-4-carboxamidehydrochloride (0.45 g, 2.34 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.2 g ofN,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxamide(Yield=25%). ¹H NMR (400 MHz, CD₃OD): δ 7.58 (m, 2H), 7.19 (d, J=8.8 Hz,1H), 7.09 (t, J=7.6 Hz, 1H), 4.32 (t, J=5.2 Hz, 2H), 3.11-2.98 (m, 4H),2.74 (s, 3H), 2.73-2.65 (m, 2H), 2.21-2.14 (m, 2H), 1.65-1.57 (m, 2H),1.19 (s, 3H); ESI+MS: m/z 345.4 ([M+H]⁺).

Example-199: N, 4-dimethyl-1-(2-phenoxyethyl)piperidine-4-carboxamide

Title compound was prepared from N,4-dimethylpiperidine-4-carboxamidehydrochloride (0.1 g, 0.52 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.05 g of N,4-dimethyl-1-(2-phenoxyethyl)piperidine-4-carboxamide(Yield=35%). ¹H NMR (400 MHz, CD₃OD): δ 7.29-7.23 (m, 2H), 6.95-6.89 (m,3H), 4.13 (t, J=5.6 Hz, 2H), 2.86-2.78 (m, 4H), 2.73 (s, 3H), 2.48-2.38(m, 2H), 2.15-2.07 (m, 2H), 1.62-1.52 (m, 2H), 1.16 (s, 3H); ESI+MS: m/z277.3 ([M+H]⁺).

Example-200:1-(2-(2-fluorophenoxy)ethyl)-N,4-dimethylpiperidine-4-carboxamide

Title compound was prepared from N,4-dimethylpiperidine-4-carboxamidehydrochloride (0.14 g, 0.53 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.054 g of1-(2-(2-fluorophenoxy)ethyl)-N,4-dimethylpiperidine-4-carboxamide(Yield=34%). ¹H NMR (400 MHz, CDCl₃): δ 7.11-6.85 (m, 4H), 5.72 (br s,1H), 4.17 (t, J=5.9 Hz, 2H), 2.85-2.78 (m, 5H), 2.76-2.70 (m, 2H),2.52-2.45 (m, 2H), 2.10-1.99 (m, 2H), 1.65-1.55 (m, 2H), 1.19 (s, 3H);ESI+MS: m/z 294.8 ([M+H]⁺).

Example-201:1-(2-(2-methoxyphenoxy)ethyl)-N,4-dimethylpiperidine-4-carboxamide

Title compound was prepared from N,4-dimethylpiperidine-4-carboxamidehydrochloride (0.14 g, 0.53 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.057 g of1-(2-(2-methoxyphenoxy)ethyl)-N,4-dimethylpiperidine-4-carboxamide(Yield=35%). ¹H NMR (400 MHz, CDCl₃): δ 6.95-6.85 (m, 4H), 5.74 (br s,1H), 4.12 (t, J=6.2 Hz, 2H), 3.83 (s, 3H), 2.83-2.77 (m, 5H), 2.73-2.66(m, 2H), 2.49-2.42 (m, 2H), 2.06-1.97 (m, 2H), 1.62-1.52 (m, 2H), 1.16(s, 3H); ESI+MS: m/z 308.8 ([M+H]⁺).

Example-202:1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,4-dimethylpiperidine-4-carboxamide

Title compound was prepared from N,4-dimethylpiperidine-4-carboxamidehydrochloride (0.3 g, 1.56 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography afforded0.06 g of1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,4-dimethylpiperidine-4-carboxamide(Yield=13%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.50-7.44 (m, 1H), 6.87-6.77(m, 4H), 4.33-4.24 (m, 2H), 3.96-3.88 (m, 1H), 2.57 (d, J=4.4 Hz, 1H),2.55-2.45 (m, 6H), 2.30-2.10 (m, 2H), 1.99-1.92 (m, 2H), 1.40-1.31 (m,2H), 1.04 (s, 3H); ESI+MS: m/z 305.3 ([M+H]⁺). The enantiomers of 202were separated using chiral HPLC (method K) and afforded the pureenantiomers 202a and 202b.

Example-203:N-cyclopropyl-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidine-4-carboxamide

tert-butyl 4-(cyclopropylcarbamoyl)-4-methylpiperidine-1-carboxylate

Title compound was prepared from1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.5 g,2.06 mmol) following the conditions reported for example 198.Purification by silica gel chromatography eluting with 7% MeOH in DCMafforded 0.5 g of tert-butyl4-(cyclopropylcarbamoyl)-4-methylpiperidine-1-carboxylate (Yield=86%).

N-cyclopropyl-4-methylpiperidine-4-carboxamide hydrochloride

Title compound was prepared from tert-butyl4-(cyclopropylcarbamoyl)-4-methylpiperidine-1-carboxylate (0.5 g, 1.77mmol) following the conditions reported for example 198 and afforded 0.3g of N-cyclopropyl-4-methylpiperidine-4-carboxamide hydrochloride(Yield=77%).N-cyclopropyl-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidine-4-carboxamide

Title compound was prepared fromN-cyclopropyl-4-methylpiperidine-4-carboxamide hydrochloride (0.3 g,1.37 mmol) using the general methodology of Example-1. Purificationusing silica gel column chromatography afforded 0.1 g ofN-cyclopropyl-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidine-4-carboxamide(Yield=22%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.45 (d, J=3.5 Hz, 1H),6.86-6.78 (m, 4H), 4.33-4.24 (m, 2H), 3.95-3.89 (m, 2H), 2.65-2.58 (m,2H), 2.50-2.44 (m, 3H), 2.24-2.09 (m, 2H), 1.99-1.92 (m, 2H), 1.36-1.28(m, 2H), 1.02 (s, 3H), 0.61-0.55 (m, 2H), 0.43-0.38 (m, 2H); ESI+MS: m/z331.1 ([M+H]⁺). The enantiomers of 203 were separated using chiral HPLC(method U) and afforded the pure enantiomers 203a and 203b.

Example-204:1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methyl-N-phenylpiperidine-4-carboxamide

Title compound was prepared from1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid and anilinefollowing the conditions reported for example 198. Purification bysilica gel chromatography afforded 0.26 g of1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methyl-N-phenylpiperidine-4-carboxamide(Yield=45%). ¹H NMR (500 MHz, DMSO-d₆): δ 9.21 (s, 1H), 7.62 (d, J=7.6Hz, 2H), 7.27 (t, J=8.0 Hz, 2H), 7.02 (t, J=7.5 Hz, 1H), 6.86-6.76 (m,4H), 4.34-4.23 (m, 2H), 3.93 (dd, J=11.3 Hz, J=6.9, Hz, 1H), 2.70-2.54(m, 2H), 2.50-2.48 (m, 2H), 2.36-2.18 (m, 2H), 2.14 (d, J=13.0 Hz, 2H),1.51-1.44 (m, 2H), 1.20 (s, 3H); ESI+MS: m/z 367.1 ([M+H]⁺). Theenantiomers of 204 were separated using chiral HPLC (method D) andafforded the pure enantiomers 204a and 204b.

Example-205:(S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,N,4-trimethylpiperidine-4-carboxamide

tert-butyl 4-(dimethylcarbamoyl)-4-methylpiperidine-1-carboxylate

To a cooled solution of N-Boc-4-methylpiperidine-4-carboxylic acid (0.50g, 2.05 mmol) at 0° C. in dry CH₂Cl₂ (7 mL) was addeddiisopropylethylamine (0.54 mL, 3.08 mmol), hydroxybenzotriazole (0.31g, 2.26 mmol) and dimethylamine hydrochloride (0.24 g, 2.88 mmol).EDC-HCl (0.43 g, 2.26 mmol) was then added at 0° C. and the mixture wasleft to warm up to room temperature and left stirring overnight. Theresulting suspension was filtered through celite and washed with DCM.The filtrate was washed with 1 N aq. sol. HCl, sat. aq. K₂CO₃, H₂O andbrine. The organic layer was dried over Na₂SO₄ and the solvent removedunder reduced pressure. The product was obtained as white powder (0.52g, 94% yield). ¹H-NMR (300 MHz, CDCl₃): δ 3.59 (br s, 2H), 3.19 (br s,2H), 3.02 (s, 6H), 2.20-2.10 (m, 2H), 1.43 (s, 9H), 1.27 (s, 3H).

N,N,4-trimethylpiperidine-4-carboxamide hydrochloride

To a solution of tert-butyl4-(dimethylcarbamoyl)-4-methylpiperidine-1-carboxylate (0.52 g, 1.92mmol) in Et₂O (2 mL) was added dropwise HCl (2 mL, 8.00 mmol, 4 Ndioxane solution) under N₂. The reaction mixture was stirred for 2 hoursand the solvent was removed under reduced pressure to obtain product aswhite solid (0.38 g, 97% yield). ¹H-NMR (300 MHz, DMSO-d₆): δ 9.20-8.75(br m, 2H), 3.56 (s, 6H), 3.20-3.02 (m, 2H), 2.82 (br s, 2H), 2.20-2.00(m, 2H), 1.71-1.55 (m, 1H), 1.20 (s, 3H). ESI-MS calcd for C₉H₁₈N₂₀ m/z170.14, found 171.61 [M+H]⁺.

(S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,N,4-trimethylpiperidine-4-carboxamide

Title compound was prepared from N,N,4-trimethylpiperidine-4-carboxamidehydrochloride (0.08 g, 0.40 mmol) using the general methodology ofexample 1. Purification by silica gel chromatography afforded 0.032 g of(S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,N,4-trimethylpiperidine-4-carboxamide(Yield=25%). [α]_(D) ²⁵=−17.1° (CHCl₃; c=0.11). ¹H NMR (300 MHz, CDCl₃):δ 6.93-6.77 (m, 4H), 4.38-4.26 (m, 2H), 3.96 (ddd, J=11.7, 7.7, 2.3 Hz,1H), 3.04 (s, 6H), 2.82-2.38 (m, 6H), 2.33 (s, 2H), 2.28-2.18 (m, 2H),1.65-1.53 (m, 2H), 1.27 (s, 3H); ESI+MS: m/z 319.6 ([M+H]⁺).

Example-206:(S)-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)(pyrrolidin-1-yl)methanone

Title compound was prepared using the same strategy employed for example205 by replacing dimethylamine hydrochloride with pyrrolidine. [α]_(D)²⁵=−11.4° (CHCl₃; c=0.26). ¹H NMR (300 MHz, CDCl₃): δ 6.92-6.78 (m, 4H),4.33-4.23 (m, 2H), 4.02-3.92 (m, 1H), 3.54 (t, J=6.8 Hz, 4H), 2.77-2.20(m, 9H), 1.86 (br s, 4H), 1.60-1.48 (m, 2H), 1.21 (s, 3H); ESI+MS: m/z319.6 ([M+H]⁺).

Example-207:(S)-1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-N-methylmethanamine

To a cooled solution of(S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,4-dimethylpiperidine-4-carboxamide(100 mg, 0.33 mmol) in an. THF (0.65 mL) at 0° C. was added lithiumaluminum hydride (12 mg, 0.33 mmol), under Ar. The mixture was stirredat room temperature overnight and then was quenched with 2 M aq. sol. ofHCl. The solution was diluted with CH₂Cl₂ and Na₂CO₃ was added until thepH of the solution was basic. The organic layer was separated and theaqueous layer was extracted with CHCl₃. Organic layers were collected,dried over Na₂SO₄ and concentrated. Purification by flash chromatography(CH₂Cl₂/CH₃OH 80:20) afforded product as colorless oil (34 mg, 36%yield). [α]_(D) ²⁵=−11.8° (CHCl₃; c=0.12). ¹H-NMR (400 MHz,Chloroform-d): δ 6.90-6.78 (m, 4H), 4.33-4.27 (m, 2H), 3.97 (dd, J=11.6,7.7 Hz, 1H), 2.70-2.63 (m, 2H), 2.63-2.53 (m, 2H), 2.51-2.46 (m, 6H),2.45-2.35 (m, 1H), 1.63-1.53 (m, 2H), 1.50-1.40 (m, 2H), 1.01 (s, 3H).ESI+MS: m/z 291.3 ([M+H]⁺).

Example-208:(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide

N-(1-benzyl-4-methylpiperidin-4-yl)acetamide

To a cooled solution of 1-benzyl-4-methylpiperidin-4-ol (0.30 g, 1.46mmol) in CH₃CN (2.2 mL, 40.9 mmol) at 0° C. was added dropwiseconcentrated H₂SO₄ (1.48 mL, 27.8 mmol) so that the temperature did notexceed 30° C. After the addition, the mixture was stirred at roomtemperature for 16 hours. For termination of the reaction the resultingoil was poured onto ice and adjusted to pH 10 with a 3 M aq. KOHsolution. The aqueous phase was extracted with CH₂Cl₂, dried overNa₂SO₄, filtered and the solvent was removed under reduced pressure. Theresulting white solid was levigated with n-hexane to obtain product(0.34 g, 94% yield). ¹H-NMR (300 MHz, DMSO-d₆): δ 7.35-7.20 (m, 5H),3.41 (s, 2H), 2.43-2.32 (m, 2H), 2.26-2.11 (m, 2H), 2.06-1.95 (m, 2H),1.78 (s, 3H), 1.42 (ddd, J=13.8, 10.1, 3.8 Hz, 2H), 1.23 (s, 3H). ESI-MScalcd for C₁₅H₂₂N₂₀ m/z 246.17, found 246.41 [M]⁺.

N-(4-methylpiperidin-4-yl)acetamide

To a degassed solution of N-(1-benzyl-4-methylpiperidin-4-yl)acetamide(0.70 g, 2.84 mmol) in CH₃OH (17 mL) was added NH₄HCO₂ (0.82 g, 13.00mmol, dried under vacuum) and Pd/C (10%, 140 mg). The mixture wasflushed with Ar and left stirring for 2 hour at 65° C. The mixture wasfiltered and solvent was removed under reduced pressure to afford theproduct as a colorless thick oil (0.42 g, 95% yield). ¹H-NMR (300 MHz,DMSO-d₆): δ 7.29 (br s, 1H), 2.68 (bs, 4H), 2.03-1.92 (m, 2H), 1.79 (s,3H), 1.40-1.26 (m, 2H), 1.23 (s, 3H). ESI-MS calcd for C₈H₁₆N₂O m/z156.13, found 157.20 [M+H]⁺.

(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide

To a stirred solution of N-(4-methylpiperidin-4-yl)acetamide (98 mg,0.62 mmol) and (R)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl4-methylbenzenesulfonate (100 mg, 0.31 mmol) in CH₃CN (1.6 mL) was addedK₂CO₃ (65 mg, 0.47 mmol) at room temperature. The reaction mixture wasstirred at 80° C. for 18 hours and then diluted with H₂O and extractedwith EtOAc. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude residue was purified by flash chromatography(CH₂Cl₂/CH₃OH 95:5) to afford pure product as white solid (72 mg, 76%yield). [α]_(D) ²⁵=−15.4° (CHCl₃; c=0.17). ¹H-NMR (300 MHz, CDCl₃): δ6.92-6.78 (m, 4H), 5.09 (br s, 1H), 4.35-4.25 (m, 2H), 3.98 (dd, J=11.6,7.6 Hz, 1H), 2.77-2.53 (m, 4H), 2.46-2.26 (m, 2H), 2.11-1.98 (m, 2H),1.96 (s, 3H), 1.75-1.62 (m, 2H), 1.40 (s, 3H). ESI-MS calcd forC₁₇H₂₄N₂O₃ m/z 304.18, found 305.34 [M+H]⁺.

Example-209:(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)cyclopropanecarboxamide

tert-butyl 4-(cyclopropanecarboxamido)-4-methylpiperidine-1-carboxylate

To a cooled solution of cyclopropanecarboxylic acid (67.6 μl, 0.85 mmol)at 0° C. in dry DCM (4 ml) was added1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (171 mg, 0.89mmol) and N,N-dimethylpyridin-4-amine (109 mg, 0.89 mmol) and themixture was stirred for 30 minutes. tert-butyl4-amino-4-methylpiperidine-1-carboxylate (200 mg, 0.933 mmol) was addedat 0° C. and the reaction mixture was left to warm up to roomtemperature and left stirring overnight. The resulting suspension wasfiltered through a pad of celite and eluted with DCM. The residue wassuccessively washed with 0.1M aq. K₂CO₃, 0.1M aq. HCl and water. Theorganic phase was dried (Na₂SO₄), filtered and concentrated to afford171 mg of tert-butyl4-(cyclopropanecarboxamido)-4-methylpiperidine-1-carboxylate as a whitefoam (Yield=71%). ESI+MS: m/z: 283.1 ([M+H]⁺).

N-(4-methylpiperidin-4-yl)cyclopropanecarboxamide hydrochloride

tert-butyl 4-(cyclopropanecarboxamido)-4-methylpiperidine-1-carboxylate(150 mg, 0.53 mmol) was dissolved in MeOH (1 ml) and HCl (4N in dioxane,2 mL) was added dropwise. The reaction mixture was stirred for 2 hoursand the solvent was removed under vacuum to afford 111 mg ofN-(4-methylpiperidin-4-yl)cyclopropanecarboxamide hydrochloride as awhite solid (Yield=quant.).

(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)cyclopropanecarboxamide

Title compound was prepared fromN-(4-methylpiperidin-4-yl)cyclopropanecarboxamide hydrochloride (0.10 g,0.46 mmol) using the general methodology of Example-1. Purificationusing silica gel column chromatography (DCM/MeOH 95/5) afforded 0.07 gof(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)cyclopropanecarboxamide(Yield=46%). [α]_(D) ²⁵=−10.8° (CHCl₃; c=0.17). ¹H NMR (300 MHz, CDCl₃):δ 6.91-6.79 (m, 4H), 5.26 (br s, 1H), 4.36-4.25 (m, 2H), 3.98 (dd,J=11.7, 7.6 Hz, 1H), 2.78-2.53 (m, 4H), 2.48-2.30 (m, 2H), 2.15-2.05 (m,2H), 1.75-1.60 (m, 2H), 1.39 (s, 3H), 1.35-1.23 (m, 1H), 0.95-0.88 (m,2H), 0.73-0.63 (m, 2H); ESI+MS: m/z: 331.4 ([M+H]⁺).

Example-210:(S)—N-(1-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide

Title compound was prepared from N-(4-methylpiperidin-4-yl)acetamidehydrochloride (0.038 g, 0.24 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (DCM/MeOH94/6) afforded 0.023 g of(S)—N-(1-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide(Yield=59%). [α]_(D) ²⁵=−15.8° (CHCl₃; c=0.29). ¹H NMR (400 MHz, CDCl₃):δ 6.78 (dd, J=8.9, 5.4 Hz, 1H), 6.60 (dd, J=9.4, 2.9 Hz, 1H), 6.54 (ddd,J=8.9, 8.1, 3.0 Hz, 1H), 5.07 (br s, 1H), 4.32-4.23 (m, 2H), 3.94 (dd,J=11.2, 7.0 Hz, 1H), 2.74-2.53 (m, 4H), 2.45-2.28 (m, 2H), 2.11-2.01 (m,2H), 1.96 (s, 3H), 1.67 (ddd, J=14.0, 9.8, 5.3 Hz, 2H), 1.40 (s, 3H);ESI+MS: m/z: 323.3 ([M+H]⁺).

Example-211:(S)—N-(1-((7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide

Title compound was prepared from N-(4-methylpiperidin-4-yl)acetamidehydrochloride (0.036 g, 0.23 mmol) using the general methodology ofExample-1. Purification using silica gel column chromatography (DCM/MeOH95/5) afforded 0.036 g of(S)—N-(1-((7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide(Yield=83%). [α]_(D) ²⁵=−15.0° (CHCl₃; c=0.33). ¹H NMR (300 MHz, CDCl₃):δ 7.02 (d, J=2.3 Hz, 1H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.73 (d, J=8.6Hz, 1H), 5.07 (br s, 1H), 4.27 (dd, J=11.7, 2.3 Hz, 2H), 3.96 (dd,J=11.8, 7.5 Hz, 1H), 2.73-2.52 (m, 4H), 2.45-2.27 (m, 2H), 2.10-2.00 (m,2H), 1.96 (s, 3H), 1.72-1.60 (m, 2H), 1.40 (s, 3H); ESI+MS: m/z: 383.3([M+H]⁺).

Example-212:(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-2,2,2-trifluoroacetamide

tert-butyl 4-methyl-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate

To a solution of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate(190 mg, 0.89 mmol) in Pyridine (0.6 ml) at 0° C. was slowly added2,2,2-trifluoroacetic anhydride (0.129 ml, 0.93 mmol) and the reactionmixture was stirred at 0° C. for 2 hours. The reaction mixture wasdiluted with DCM, washed with brine, dried over Na₂SO₄, filtered andconcentrated. Purification by silica gel chromatography afforded 247 mgof tert-butyl4-methyl-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate(Yield=90%). ESI-MS: m/z: 309.3 ([M−H]⁻).

2,2,2-trifluoro-N-(4-methylpiperidin-4-yl)acetamide hydrochloride

A solution of HCl 4N in dioxane (0.8 ml, 3.18 mmol) was added totert-butyl 4-methyl-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate(247 mg, 0.80 mmol) and the mixture was left stirring for 1 h at 25° C.The solvents were removed under reduced pressure and afforded 0.2 g of2,2,2-trifluoro-N-(4-methylpiperidin-4-yl)acetamide hydrochloride as awhite solid (Yield=quant.). ESI-MS: m/z: 245.1 ([M−H]⁻).

(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-2,2,2-trifluoroacetamide

Title compound was prepared from2,2,2-trifluoro-N-(4-methylpiperidin-4-yl)acetamide hydrochloride (0.19g, 0.77 mmol) using the general methodology of Example-1. Purificationusing silica gel column chromatography (DCM/MeOH 95/5) afforded 0.08 gof(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-2,2,2-trifluoroacetamide(Yield=44%). [α]_(D) ²⁵=−14.7° (CHCl₃; c=0.102). ¹H NMR (400 MHz,CDCl₃): δ 6.90-6.80 (m, 4H), 5.88 (br s, 1H), 4.34-4.25 (m, 2H), 3.99(dd, J=11.7, 7.6 Hz, 1H), 2.80-2.55 (m, 4H), 2.43-2.26 (m, 2H),2.15-2.05 (m, 2H), 1.82-1.72 (m, 2H), 1.45 (s, 3H); ESI+MS: m/z: 359.3([M+H]⁺).

Example-213:(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-N-methylacetamide

tert-butyl 4-methyl-4-(N-methylacetamido)piperidine-1-carboxylate

A solution of tert-butyl 4-acetamido-4-methylpiperidine-1-carboxylate(0.25 g, 0.98 mmol) in an. DMF (3.25 ml) was added sodium hydride (0.047g, 1.17 mmol) at 0° C. and was left stirring for 1 hour at 40° C.Iodomethane (0.091 ml, 1.46 mmol) was added dropwise and the reactionwas stirred at room temperature for 2 hours. Then 10% aq. NaHCO₃ (25 mL)was added and the mixture was extracted with Et2O and the collectedorganic phases were washed with 0.1 M aq. HCl, water and brine. Theorganic phase was dried (MgSO₄), filtered and concentrated. Purificationby silica gel chromatography (Hexane/EtOAc 7:3) afforded 164 mg oftert-butyl 4-methyl-4-(N-methylacetamido)piperidine-1-carboxylate as awhite solid (Yield=62%). ESI+MS: m/z: 271.4 ([M+H]⁺).

N-methyl-N-(4-methylpiperidin-4-yl)acetamide hydrochloride

A solution of HCl in dioxane (0.6 mL, 2.22 mmol) was added to tert-butyl4-methyl-4-(N-methylacetamido)piperidine-1-carboxylate (150 mg, 0.56mmol) in MeOH (1.1 mL) and the mixture was left stirring for 1 h at 25°C. The solvents were removed under reduced pressure and afforded 0.12 gof N-methyl-N-(4-methylpiperidin-4-yl)acetamide hydrochloride as a whitesolid (Yield=quant.).

(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-N-methylacetamide

Title compound was prepared fromN-methyl-N-(4-methylpiperidin-4-yl)acetamide hydrochloride (0.09 g, 0.44mmol) using the general methodology of Example-1. Purification usingsilica gel column chromatography (DCM/MeOH 95/5) afforded 0.036 g of(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-N-methylacetamide(Yield=83%). [α]_(D) ²⁵=−8.7° (CHCl₃; c=0.16). ¹H NMR (400 MHz, CDCl₃):δ 6.88-6.80 (m, 4H), 4.32-4.21 (m, 2H), 4.02 (ddd, J=17.2, 11.1, 6.2 Hz,1H), 3.78-3.67 (m, 1H), 3.63-3.40 (m, 2H), 3.39-3.20 (m, 1H), 2.73-2.55(m, 2H), 2.27 (s, 3H), 2.09 (s, 3H), 1.80-1.68 (m, 2H), 1.45-1.30 (m,2H), 0.93 (s, 3H); ESI+MS: m/z: 319.3 ([M+H]⁺).

Example-214:(4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)methanol

methyl4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxylate

To a stirred solution of methyl1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxylate (0.2 g,0.6 mmol) in THF (2 mL) was added NaHMDS (1M solution in THF, 0.73 mL)at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Asolution of p-chlorobenzyl bromide 0.15 g, 0.72 mmol) in THF (1 mL) wasadded at −78° C. The reaction mixture was allowed to warm to roomtemperature and was stirred for 16 h. Water was added to the reactionmixture and extracted with EtOAc. The organic layer was separated, driedover Na₂SO₄, filtered and concentrated. Purification by columnchromatography eluting with 1% MeOH in DCM afforded 36 mg of methyl4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxylateas thick syrup (Yield=13%). ESI+MS: m/z: 456.1 ([M+H]⁺).

(4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)methanol

To a stirred solution of methyl4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxylate(0.1 g, 0.22 mmol) in DCM (2 mL) was added DIBAL (1.0 M solution intoluene) at 0° C. The reaction mixture was stirred at room temperaturefor 16 h. The reaction was quenched with cold water and extracted withDCM. The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated. Purification by column chromatography eluting with 8% MeOHin DCM afforded 40 mg of(4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)methanolas colorless syrup (Yield=43%). ¹H NMR (400 MHz, CD₃OD): δ7.58-7.54 (m,2H), 7.27-7.24 (m, 2H), 7.20-7.17 (m, 3H), 7.07 (t, J=7.6 Hz, 1H). 4.28(t, J=5.6 Hz, 2H), 2.99 (t, J=5.2 Hz, 2H), 2.88-2.82 (m, 2H), 2.77-2.68(m, 4H), 1.60-1.50 (m, 4H); ESI+MS: m/z: 428.1 ([M+H]⁺).

Example-215:4-(4-chlorobenzyl)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carbaldehyde

To a stirred solution of(4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)methanol(0.3 g, 0.7 mmol) in DCM (10 mL) was added PCC (0.3 g, 1.4 mmol) at 0°C. The reaction mixture was stirred at room temperature for 5 h. Aftercompletion, the reaction was diluted with DCM, filtered through celitebed and washed with DCM. The filtrate was concentrated under reducedpressure. Purification by flash chromatography eluting with 3% MeOH inDCM afforded 0.2 g of4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carbaldehydeas thick syrup (Yield=67%). ESI+MS: m/z: 426.0 ([M+H]⁺).

4-(4-chlorobenzyl)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine

To a stirred solution of4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carbaldehyde(0.2 g, 0.47 mmol) in ethylene glycol (1 mL) was added hydrazine hydrate(0.07 g, 1.4 mmol) followed by NaOH (0.056 mg, 1.4 mmol) at roomtemperature. The reaction mixture was heated at 180° C. for 16 h. Aftercompletion, the reaction was diluted with cold water and extracted withEtOAc. The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated. Purification by silica gel chromatography eluting with 2%MeOH in DCM followed by Preparative HPLC afforded 45 mg of4-(4-chlorobenzyl)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidineas colorless syrup (Yield=23%). ¹H NMR (400 MHz, CD₃OD): δ 7.59-7.53 (m,2H), 7.27-7.23 (m, 2H), 7.19-7.11 (m, 3H), 7.05 (t, J=7.6 Hz, 1H), 4.25(t, J=5.6 Hz, 2H), 2.89 (t, J=5.6 Hz, 2H), 2.83-2.77 (m, 2H), 2.58 (s,2H), 2.54 (t, J=9.6 Hz, 2H), 1.64-1.56 (m, 2H), 1.40-1.34 (m, 2H), 0.90(s, 3H); ESI+MS: m/z: 412.0 ([M+H]⁺).

Example-216:1-(4-chlorophenyl)-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octane

To a solution of4-(4-chlorobenzylidene)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine(0.1 g, 0.25 mmol) in diethyl ether (15 mL) was added diazomethane (10mL) at 0° C. and the reaction mixture was stirred for 2 h at 0° C.Pd(OAc)₂ (57 mg, 0.25 mmol) was then added and the reaction was stirredfor 2 h. After completion, the reaction mass was diluted with diethylether and filtered through a celite bed and the filtrate wasconcentrated under reduced pressure. Purification by Preparative HPLCafforded 7 mg of1-(4-chlorophenyl)-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octaneas a thick syrup (Yield=7%). ¹H NMR (400 MHz, CD₃OD): δ 7.58-7.53 (m,2H), 7.24-7.21 (m, 2H), 7.18-7.14 (m, 3H), 7.05 (t, J=7.6 Hz, 1H), 4.23(t, J=5.6 Hz, 2H), 2.90-2.83 (m, 2H) 2.82-2.70 (m, 2H), 2.52-2.38 (m,2H), 1.99-1.95 (m, 1H), 1.70-1.58 (m, 2H), 1.30-1.20 (m, 2H), 0.97-0.94(m, 1H), 0.87-0.82 (m, 1H); ESI+MS: m/z: 410.4 ([M+H]⁺). The enantiomersof 216 were separated using chiral HPLC (method N) and afforded the pureenantiomers 216a and 216b.

Example-217:N-cyclohexyl-N,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-amine

tert-butyl 4-(cyclohexylamino)-4-methylpiperidine-1-carboxylate

To a stirred solution of tert-butyl4-amino-4-methylpiperidine-1-carboxylate (0.3 g, 1.4 mmol) andcyclohexanone (0.14 g, 1.4 mmol) in ethanol (5 mL) was added Ti(iOPr)₄(1.2 g, 4.2 mmol) at room temperature. The reaction mixture was stirredat 80° C. for 16 h. Then NaBH₄ was added at room temperature and thereaction mixture was heated at 80° C. for 24 h. The reaction wasquenched with water and diluted with EtOAc. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto obtain crude material. The crude residue was purified by silica gelcolumn chromatography with 1% MeOH in DCM to afford 0.08 g of tert-butyl4-(cyclohexylamino)-4-methylpiperidine-1-carboxylate as colorless syrup(Yield=20%). ESI+MS: m/z: 297.4 ([M+H]⁺).

tert-butyl 4-(cyclohexyl(methyl)amino)-4-methylpiperidine-1-carboxylate

To a stirred solution of tert-butyl4-(cyclohexylamino)-4-methylpiperidine-1-carboxylate (0.15 g, 0.51 mmol)in DCM (5 mL) was added 37% aq. formaldehyde (0.13 mL, 1.52 mmol) at 0°C. Then NaBH(OAc)₃ (0.21 g, 1.01 mmol) was added at 0° C. and thereaction was allowed to warm to room temperature and stirred for 16 h.The reaction was quenched with 2N NaOH and extracted with DCM. Theorganic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. Purification by flash chromatography eluting with 20%EtOAc in Hexane afforded 0.1 g of tert-butyl4-(cyclohexyl(methyl)amino)-4-methylpiperidine-1-carboxylate as thicksyrup (Yield=64%). ESI+MS: m/z: 311.4 ([M+H]⁺).

N-cyclohexyl-N,4-dimethylpiperidin-4-amine hydrochloride

To a stirred solution of tert-butyl4-(cyclohexyl(methyl)amino)-4-methylpiperidine-1-carboxylate (0.1 g,0.32 mmol) in MeOH (1 mL) was added 4M HCl in 1,4-Dioxane (0.4 mL, 1.6mmol) at 0° C. The reaction mixture was stirred at room temperature for4 h. After completion of the reaction, volatiles were concentrated underreduced pressure to afford 60 mg ofN-cyclohexyl-N,4-dimethylpiperidin-4-amine hydrochloride (Yield=75%).

N-cyclohexyl-N,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-amine

Title compound was prepared fromN-cyclohexyl-N,4-dimethylpiperidin-4-amine hydrochloride (0.06 g, 0.24mmol) using the general methodology of Example-1. Purification usingsilica gel column chromatography afforded 0.03 g ofN-cyclohexyl-N,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-amine(Yield=31%). ¹H NMR (400 MHz, CD₃OD): δ 7.59-7.53 (m, 2H), 7.17 (d,J=8.8 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 4.24 (t, J=5.5 Hz, 2H), 2.86 (t,J=5.5 Hz, 2H), 2.80-2.70 (m, 3H), 2.57-2.49 (m, 2H), 2.22 (s, 3H),1.93-1.84 (m, 2H), 1.79-1.74 (m, 2H), 1.71-1.50 (m, 5H), 1.48-1.36 (m,2H), 1.34-1.25 (m, 2H), 1.15-1.06 (m, 1H), 1.04 (s, 3H); ESI+MS: m/z:399.0 ([M+H]⁺).

Example-219:4-methyl-N-phenyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxamide

Title compound was prepared using the same strategy employed for example205 by replacing dimethylamine hydrochloride with aniline. ¹H NMR (400MHz, CD₃OD): δ 7.57-7.49 (m, 4H), 7.31 (t, J=8.4 Hz, 2H), 7.16 (d, J=8.4Hz, 1H), 7.10 (t, J=7.2 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 4.25 (t, J=5.6Hz, 2H), 3.33-3.30 (m, 1H), 2.90-2.80 (m, 4H), 2.52 (t, J=9.6 Hz, 2H),2.27-2.22 (m, 2H), 1.67-1.60 (m, 2H), 1.30 (s, 3H); ESI+MS: m/z 407.5([M+H]⁺).

Example-220:1-(2-(2-fluorophenoxy)ethyl)-4-methyl-N-phenylpiperidine-4-carboxamide

Title compound was prepared using the same strategy employed for example219 by replacing 1-(2-bromoethoxy)-2-(trifluoromethyl)benzene with1-(2-bromoethoxy)-2-fluorobenzene. ¹H NMR (400 MHz, DMSO-d₆): δ 9.27 (brs, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.29 (t, J=8.0, 2H), 7.23-7.18 (m, 2H),7.12 (t, J=8.0 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.98-6.91 (m, 1H), 4.18(br s, 2H), 2.90-2.66 (m, 4H), 2.32-2.10 (m, 4H), 1.60-1.45 (m, 2H),1.23 (s, 3H); ESI+MS: m/z 357.0 ([M+H]⁺).

Example-221: Chiral Separation Using HPLC

Mixtures of stereoisomers (e.g., enantiomers or diastereomers) describedherein were separated with one of Method A to Method R of chiral HPLC.The earlier-eluted stereoisomer was designated with “a”, and thelater-eluted stereoisomer was designated with “b”. For example,enantiomers of 203 were separated using chiral HPLC, Method U, andafforded the pure enantiomers 203a and 203b, wherein 203a was theearlier-eluted stereoisomer, and 203b was the later-eluted stereoisomer.

Method A: Column: Chiralpak ADH (250×4.6 mm, 5 μm)

Eluent A: n-Hexanes

Eluent B: Ethanol

Elution using A:B 75:25 at 1 ml/min

Method B: Column: Chiralpak ADH (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: Ethanol

Elution using A:B 80:20 at 1 ml/min

Method C: Column: Chiralpak IA (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: DCM/Methanol 80:20

Elution using A:B 98:2 at 1 ml/min

Method D: Column: Chiralpak ADH (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: Ethanol/Methanol 50:50

Elution using A:B 75:25 at 1 ml/min

Method E: Column: Chiralpak IC (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: DCM/Methanol 50:50

Elution using A:B 90:10 at 1 ml/min

Method F: Column: Chiralpak IC (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: Ethanol

Elution using A:B 95:5 at 1 ml/min

Method G: Column: Chiralpak IA (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: DCM/Methanol 50:50

Elution using A:B 90:10 at 1 ml/min

Method H: Column: Chiralpak IB (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: DCM/Methanol 50:50

Elution using A:B 90:10 at 1 ml/min

Method I: Column: Chiralpak IA (250×4.6 mm, 5 μm)

Eluent A: n-Hexanes

Eluent B: DCM/Methanol 50:50

Elution using A:B 80:20 at 1 ml/min

Method J: Column: Chiralpak IA (250×4.6 mm, 5 μm)

Eluent A: n-Hexanes

Eluent B: Ethanol

Elution using A:B 70:30 at 1 ml/min

Method K: Column: Chiralpak ADH (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: Ethanol

Elution using A:B 85:15 at 1 ml/min

Method L: Column: Chiralpak IA (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: Isopropanol

Elution using A:B 90:10 at 1 ml/min

Method M: Column: Chiralpak IA (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: Ethanol

Elution using A:B 85:15 at 1 ml/min

Method N: Column: Chiralcel ODH (250×4.6 mm, 5 μm)

Eluent A: 0.1% TFA in n-Hexanes

Eluent B: Ethanol/Methanol 50:50

Elution using A:B 90:10 at 1 ml/min

Method P: Column: Chiralpak ADH (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: Isopropanol

Elution using A:B 90:10 at 1 ml/min

Method R: Column: Chiralpak IB (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: Isopropanol

Elution using A:B 95:5 at 1 ml/min

Method S: Column: Chiralpak ADH (250×4.6 mm, 5 μm)

Eluent A: 0.1% TFA in n-Hexanes

Eluent B: Ethanol/Methanol 50:50

Elution using A:B 95:5 at 1 ml/min

Method T: Column: Chiralpak IC (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Hexanes

Eluent B: DCM/Methanol 80:20

Elution using A:B 99:1 at 1 ml/min

Method U: Column: Chiralpak ODH (250×4.6 mm, 5 μm)

Eluent A: 0.1% DEA in n-Heptane

Eluent B: Ethanol

Elution using A:B 80:20 at 1 ml/min

Example-222: Biological Activity

Suitable cell lines for use in the below assays, e.g., Gi/cAMP andβ-arrestin assays include CHO-K1 cell expressing human D2R/β-arrestin(purchased from DiscoveR_(x)). The cell lines were grown or maintainedin growth media comprising Ham's F-12 (Cellgro 10-080-CV), 10% HI FBS(Gibco 16140), 1×Penn/Strep/Glutamine (Gibco #10378), 600 ug/mlGeneticin (Gibco #10131) and 300 ug/ml Hygromycin (Invitrogen10687-010).

Cells were prepared for assays by growing cultures for up to 2 weeks(from about 6-20 passages). A vial of frozen cells was thawed in a waterbath held at 37° C. The cells were then transferred into a 50 ml tubewith 10 ml growth media. The vial was rinsed with growth media and thecontents transferred to the 50 ml tube. The 50 ml tube was centrifugedat 1200 rpm for 5 minutes at room temperature. The supernatant wasdecanted and the pellet of cells were re-suspended in growth media andgrown at 37° C., 95% humidity, 5% CO₂. When the cells reached about 90%confluence (approximately 3 days between passages), the cells werepassaged and used for either the agonist or antagonist assays asdescribed below.

β-Arrestin Agonist Assay

The cells were prepared for β-arrestin assays as described above. Theassays were performed using a PathHunter® β-Arrestin Detecting Kit(DiscoveR_(x)). The cells were grown on 225 mm dishes, then washed oncewith 1×PBS (Cellgro), followed by digestion with 2.5 ml 1× Detachmentreagent (DRX 92-0009) for approximately 2 minutes. Plating 2 reagent((DRX 93-0563R2B, 10 ml) was added to the plate, and the cells weretransferred into a 50 ml centrifuge tube and centrifuged at roomtemperature using BD Dynac III at 1200 rpm for 5 minutes. Thesupernatant was decanted and the pellet was re-suspended in Plating 2reagent at an optimized density of 2.5×10⁵ cells/ml. The cells were thenplated onto white 384 well plates, to a final cell density of 5000cells/20 μl/well. The plates were then transferred to a humidifiedincubator maintained at 37° C., 5% CO₂, and incubated for 24 hours priorto testing. The compounds were then pin-transferred (100 nL) to thecells, and was incubated for 90 minutes at 37° C. The detection reagent(9.6 μL, Buffer: Emerald II: Galactor-Star in a 19:5:1 ratio, i.e.,14.06 mL: 3.7 mL: 0.74 mL=18.5 mL) was then added to the agonist plates.The plates were then incubated for 60 minutes at room temperature in thedark, before reading the assay results using the protocol Luminescence(Aperture luminescence 384-well) on an EnVision® detection instrument(Perkin Elmer).

β-Arrestin Antagonist Assay

The cells were prepared for β-arrestin assays as described above. Theassays were performed using a PathHunter® β-Arrestin Detecting Kit(DiscoveR_(x)). The cells were grown on 225 mm dishes, then washed oncewith 1×PBS (Cellgro), followed by digestion with 2.5 ml 1× Detachmentreagent (DRX 92-0009) for approximately 2 minutes. Plating 2 reagent((DRX 93-0563R2B, 10 ml) was added to the plate, and the cells weretransferred into a 50 ml centrifuge tube and centrifuged at roomtemperature using BD Dynac III at 1200 rpm for 5 minutes. Thesupernatant was decanted and the pellet was re-suspended in Plating 2reagent at an optimized density of 2.5×10⁵ cells/ml. The cells were thenplated onto white 384 well plates, to an optimized final cell density of5000 cells/20 μl/well. The plates were then transferred to a humidifiedincubator maintained at 37° C., 5% CO₂, and incubated for 24 hours priorto testing. The compounds were then pin-transferred (100 nL) to thecells, and incubated for 10 minutes at 37° C., before addition ofQuinpirole (5 uL of a 650 nM solution, 78.5 μl of quinpirole (100 μM inDMSO) into 12 mL Plating 2 reagent) to each well, to final concentrationof 130 nM. The plates were then incubated for 90 minutes at 37° C.before addition of the detection reagents (12 μL, Buffer: Emerald II:Galactor-Star=19:5:1 ratio 14.06 mL:3.7 mL:0.74 mL=18.5 mL) to theplates. The plates were then incubated for 60 minutes at roomtemperature in the dark before reading the assay results using theprotocol Luminescence (Aperture luminescence 384-well) on an EnVision®detection instrument (Perkin Elmer).

Gi/cAMP Agonist Assay

The cells were prepared for Gi/cAMP assays as described above. Theassays were performed using a PE Lance Ultra cAMP kit (TRF0263). Thecells were grown on 225 mm dishes, then washed once with 1×PBS (Cellgro)before digestion with 2.5 ml 1× Detachment reagent (DRX 92-0009) forabout 2 minutes. PBS (20 ml) was then added to the plate, and the cellswere transferred to a 50 ml centrifuge tube, and centrifuged at roomtemperature using BD Dynac III, at 1200 rpm for 5 minutes. Thesupernatant was decanted and the pellet was re-suspended in stimulationbuffer at an optimal density of 6.67×10e5 cells/ml, before plating ontowhite 384 well plates (15 μl/well) to a final concentration of 10,000cells/15 μl/well. Compounds were pin-transferred (100 nL) to the cells,and incubated for 10 min. at 37° C. Forskolin (5 μl of a 10 μM solution,12 μL Forskolin (10 mM in DMSO) into 12 mL Stimulation buffer) was thenadded to each well to final concentration to 2.5 μM Forskolin, and theplates were then incubated at room temperature for 30 minutes. Eu-cAMPtracer solution (10 μl, PerkinElmer, 360 μl of Tracer in 17.64 ml kitbuffer) and ULight-anti-cAMP solution (10 μl, 120 μL antibody in 17.88ml kit buffer) was then added to each well. The plates were thenincubated at room temperature for about 1 hr in the dark before readingthe assay results using protocol Lance (Excitation 320 nm, Emissionfilter 665 nm, second emission filter 615 nm, Top mirror Lance Delfia)on an EnVision® detection instrument (Perkin Elmer).

Gi/cAMP Antagonist Assay

The cells were prepared for Gi/cAMP assays as described above. Theassays were performed using a PE Lance Ultra cAMP kit (TRF0263). Thecells were grown on 225 mm dishes, then washed once with 1×PBS (Cellgro)before digestion with 2.5 ml 1× Detachment reagent (DRX 92-0009) forabout 2 minutes. PBS (20 ml) was then added to the plate, and the cellswere transferred to a 50 ml centrifuge tube, and centrifuged at roomtemperature using BD Dynac III, at 1200 rpm for 5 minutes. Thesupernatant was decanted and the pellet was re-suspended in stimulationbuffer at an optimized density of 6.67×10e5 cells/ml, before platingonto white 384 well plates (15 μl/well) to a final concentration ofabout 10,000 cells/15 μl/well. Chemical plate was pin-transferred (100nL) to the cells, and incubated for 10 min. at 37° C. A 5 μl mixturecontaining Forskolin (10 μM, 12 L Forskolin (10 mM in DMSO) into 12 mLstimulation buffer) and Quinpirole (10.8 nM, 131 L Quinpirole (1 μM inDMSO) into 12 mL Forskolin buffer) were added to each well to a finalconcentration of 2.5 μM Forskolin and 2.7 nM Quinpirole. The plates werethen incubated at room temperature for about 30 minutes before additionof Eu-cAMP tracer solution (10 μl, PerkinElmer) and thenULight-anti-cAMP solution (10 μl) to each well. Following incubation atroom temperature for 1 hr in the dark, the assay results were read usingprotocol Lance (Excitation 320 nm, Emission filter 665 nm, secondemission filter 615 nm, Top mirror Lance Delfia) on an EnVision®detection instrument (Perkin Elmer).

Pharmacokinetic Studies on Mice Brains

Twelve male C57BL/6 mice were weighed and administered intraperitoneallywith a dose of test compound (Examples 90, 157, 125) solutionformulation. The dosing volume administered for the intraperitonealroute was at 10 mL/kg. Blood samples (approximately 60 L) were collectedfrom retro-orbital plexus of each mouse under light isofluraneanesthesia at 0.08, 0.5, 1, 2, 4, and 8 hr. Following the collection ofblood, plasma was also harvested by centrifugation and stored at −70° C.until analysis. After collection of plasma, the animals were euthanizedand brain samples were isolated at 0.08, 0.5, 1, 2, 4, and 8 hr. Tissuesamples (brain) were homogenized using ice-cold phosphate buffer saline(pH 7.4) and homogenates were stored below −70° C. until analysis. Totalhomogenate volume was three times the tissue weight. Concentrations oftest compound in mouse plasma and brain samples were determined byLC-MS/MS method.

Identical extraction procedures were used for the plasma/brainhomogenate study samples and the spiked plasma calibration standards: A25 μL sample of either study sample (plasma/brain) or spiked calibrationstandard was added to individual pre-labeled micro-centrifuge tubes. Avolume of 100 μL of IS (antipyrine, 500 ng/mL) prepared in acetonitrilewas then added to the micro-centrifuge tubes, except in a sample used asa negative control where only acetonitrile was added and vortexed for 5minutes. Samples were centrifuged for 20 minutes at the speed of 4000rpm at 4° C. Following centrifugation, 100 μL of the supernatant wassampled from each centrifuge tube and transferred into insert vials.These vials remained within the auto-sampler for the LC/MS/MS analysis.Standards used for calibration were prepared by spiking 10 μL of thetest compound in 190 μL of control (used as a negative control) mouseplasma/brain homogenate.

The plasma and brain concentration-time data of test compounds wasprovided for data analysis. The plasmaand brain concentration-time datawas then used for the pharmacokinetic analysis.Non-Compartmental-Analysis module in Phoenix® WinNonlin® (Version 6.3)was used to assess the pharmacokinetic parameters. Peak plasmaconcentrations (C_(max)) and time for the peak plasma concentrations(T_(max)) were the observed values. The areas under the concentrationtime curve (AUC_(last) and AUC_(inf)) were calculated by lineartrapezoidal rule. The terminal elimination rate constant, ke wasdetermined by regression analysis of the linear terminal portion of thelog plasma concentration-time curve.

Illustrative results are presented in FIG. 2, the pharmacokineticparameters are as follow

Plasma Brain Brain AUC T_(1/2) Cmax AUC T_(1/2) Cmax B/P B/P Proteinμmol/L · Hr hr μmol/L μmol/L · Hr hr μmol/L Cmax AUC Binding Compound 904.4 4.7 1.44 34.2 4.2 7.23 5.0 7.8 >99.9% Compound 157 14.0 6.2 2.4770.4 6.0 7.03 2.9 5.0 >99.9% Compound 125 69.6 13.4 19.8 222.3 7.0 37.91.9 3.2 99.8%

Positron Emission Tomography Studies on Rodents

All animal procedures were performed in accordance with the NationalInstitutes of Health Guide for the Care and Use of Laboratory Animalsand were approved by the Massachusetts General Hospital InstitutionalAnimal Care and Use Facility. Male Sprague-Dawley rats (8-14 weeks old,Charles River Labs) were used for the study with animals pair-housed ona diurnal 12:12 light/dark cycle with free access to food and water. Therats were stabilized under anesthesia (2% isoflurane in 1.5 L/minoxygen) before an intravenous (i.v.) catheter was placed in the lateraltail vein (BD Angiocath #381112, 24G) and non-radiolabeled testcompounds were administered 5-180 minutes prior to radiotraceradministration. All test compounds (vehicle, compound of Example 90,Clozapine) were solubilized in a solution of (10% DMSO, 10% Tween-80,80% saline) and injected at a volume≤2 mL/kg. Baseline control scanswere obtained from pretreatment time-matched control animalsadministered an equivalent volume of vehicle alone. Respiration of eachanimal was monitored for the duration of the procedure.

Carbon 11-labeled raclopride ([¹¹C]RAC) was synthesized from theO-desmethyl RAC precursor and [11C] methyl iodide and subsequentlypurified by high-performance liquid chromatography as previouslydescribed (Farde L, et al. (1985) PNAS, USA 82(11):3863-3867).

For each scan, 1.0±0.15 mCi [¹¹C]RAC radiotracer was administered viai.v. catheter in a volume≤1.5 mL in a vehicle containing (10% ethanol,90% saline). Positron emission tomography (PET) and skeletal computedtomography (CT) data were collected using a GammaMedica Triumph trimodalPET/SPECT/CT scanner (Quebec, Canada) or PET data alone using a ConcordeMicrosystems R4 microPET scanner (Knoxville, Tenn., USA). Each [¹¹C]RACscan included subtraction of random coincidences collected in a delayedtime window. Scatter-corrected sinograms were reconstructed using a3-dimensional iterative maximum likelihood expectation maximization(3D-MLEM) algorithm with 16 iterations yielding an image resolution of˜1.5 mm FWHM (Full Width at Half Maximum). Pixel size in reconstructedimages was 0.26 mm transaxially, 0.6 mm slice thickness. Regions ofInterest (ROIs) were drawn on reconstructed images estimating peak[¹¹C]RAC uptake in striata (averaged between left and right hemispheres)and cerebellum as reference region for non-displaceable (ND) traceruptake. ROI dimensions, placement and striatal D2/D3 binding potential(BP_(ND)) were evaluated by graphical analysis using Logan distributionvolume ratio (DVR) linearization as previously described(BP_(ND).=DVR-1; Alexoff D, et al. (2002) JNucMed 44(5): 815-822; LoganJ, et al. (1996) JCerebral Blood Flow and Metabolism 16(5):843-840).

Illustrative results are presented in FIG. 3.

Amphetamine Induced Hyperactivity Studies

Amphetamine-induced hyperactivity (AIH) was examined in eight identicalopen-field chambers (16.5″×16″×12″; AccuScan Instruments, Columbus,Ohio). Activity was detected by infrared beam breaks and recordedautomatically by VersaMax software (AccuScan). Daily sessions wereautomatically binned in 5 minute intervals (VersaDat; AccuSacn) forstatistical analysis. AIH was run over three consecutive days asfollows:

Day 1: Mice were acclimated to the injection procedure by injecting 30minutes prior to being placed in the chambers (to match the timing ofday 3 compound administration). Mice were then placed into theopen-field for 20 minutes and then removed for a saline injection (tomatch the timing of amphetamine administration on day 3). Mice wereplaced back into the open-field for an additional 30 minutes, at whichpoint the mice were returned to their home cage.

Day 2 was run identically to Day 1, with the exception that the secondday lasted for one hour (20 minutes→injection→40 minutes).

Day 3 was the amphetamine challenge day. Mice were pre-treated with D2antagonist compounds (compound of Example 90) 30 minutes prior to beingplaced in the open field. After 20 minutes, mice were removed andchallenged with amphetamine, following protocols known to one skilled inthe art, for example Jones C. A, et. al. Br J Pharmacol. 2011, 164(4):1162-1194; Pan J Q, et. al. Neuropsychopharmacology. 2011,36(7):1397-1411.

Illustrative results are presented in FIG. 4.

Rotarod Performance

In the test, mice are placed on a horizontally oriented, rotatingcylinder (rod) suspended above a cage floor, which is low enough not toinjure the animal, but high enough to induce avoidance of fall. The micenaturally try to stay on the rotating cylinder, or rotarod, and avoidfalling to the ground. Mice are administered clozaril at 3 mg/kg (testgroup); or a compound of Formula (I) (either 10 mg/kg or 30 mg/kg orvehicle). The mice have an average weight of 20 grams (as do the mice inall examples herein). The length of time that a given animal stays onthis rotating rod is a measure of the animal's balance, coordination,physical condition, and motor-planning. The speed of the rotarod ismechanically driven, and is held constant.

Heatmap

The heatmap of FIG. 5 represents binding across various relevant CNSbiological targets including GPCRs, transporters, etc. for clozapine,aripiprazole and amisulpride, alongside exemplary compounds of theinvention—Examples 90, 157, 125, and 99.

Results of Gi/cAMP and β-Arrestin Antagonist and Agonist Assays UsingCHO-K1 Cell Line Expressing Human D2R/β-Arrestin

Herein exemplified compounds were analyzed by way of the foregoingGi/cAMP and 3-arrestin antagonist and agonist assays using CHO-K1 cellline expressing human D2R/β-arrestin and thus both the Gi/cAMP andβ-arrestin pathways were monitored in both agonist and antagonist(Quinpirole was used as agonist) modes. FIG. 1 shows representativecurves obtained for selected D2 ligands: Clozapine, Aripiprazole, andcompounds of the invention 90, 157, 158, and 125. Compounds 90, 157 and158 are representative β-arrestin biased D2R antagonists. Compound 125is a representative cAMP-biased agonist. Table 1 tabulates the resultsas to the various exemplified compounds, in dopamine β-arrestin and cAMPassays in agonist and antagonist modes. In table 1, Emax is higher than20%.

TABLE 1 Biological data from testing compounds in the foregoing Gi/cAMPand β-arrestin antagonist and agonist assays using CHO-K1 cell lineexpressing human D2R/β-arrestin. Both the Gi/cAMP and β-arrestinpathways were monitored in both agonist and antagonist (quinpirole usedas agonist) modes. The D2 binding Ki values were determined using aradioligand binding assay. EC₅₀ or IC₅₀ values were categorized asfollows. Emax values for a given pathway ranged from 10-100%. D2 bindingβ-arrestin cAMP β-arrestin cAMP Compound # K_(i) Antagonist AntagonistAgonist Agonist Aripiprazole A A A A A Clozapine B B B E E Cariprazine AE A A UNC9994 B or C E B or C A UNC9975 B or A B E B or A D,L- A A E EStepholidine Quinpirole E E B or A A Dopamine E E B or C A Apomorphine EE A A MLS1547 C E E A  1 C C E E A  1a B E E A  1b C A E B  2 B B E E  3C B E E  4 C B E E  5 B A E E  6 C B E E  7 D E E E E  7a E E E E  7b EE E C  8 C B E E  9 B E E A  10 C E E A  11 C B E A  12 E E A A  12a B EA A  12b E E A A  13 C B E E  14 C B E A  15 C C E A  16 C E E B  17 D CE E  18 C E E B  18a C E E A  18b C C E E B  19 E E C A  20 D E E A  21C C E E  22 C B E A  23 B E E A  24 E E A A  25 C C E E  26 C B E E  27B C B E E  28 B A E E  29 C C E E  30 E E C B  31 C B E E  32 C E E B 33 C B E E  34 E E C B  35 C E E A  36 C B E B  37 C B E E  38 E E B A 39 B E E A  40 C E E B  41 D E E B  42 C E E A  43 C E E E  44 E E B A 45 C E E A  47 C E E B  48 D E E A  49 D E E B  50 D E E A  51 B E E A 52 C E E A  53 C E E A  54 C C D E B  55 C C E E A  55a C B E E  55b DE E A  56 C C E A  57 C E E B  58 E E C A  59 C E E D A  59a D E E B 59b D E E C A  60 E E B A  61 C B E E  62 C C E E  63 C C E E  64 D E EB  65 C B E E  66 C D E A  67 B E E A  68 B E E E A  69 B E A A  70 B DE A  71 B B E E  72 B A E A  73 E E E E  74 B E B A  75 B B E E  76 B EE A  77 E E E D  78 B B C E D  80 C C E D  81 D E E C  83 C B E E  84 CE E C  85 C E E A  86 A E E A A  87 E E A A  88 A E A A  89 A E A A  90B B E C A  91 B A E E A  92 C B E A  93 C B E B  94 C C E B  96 B B A EE  96a C B E E  96b C B E E  97 B A E E  98 B A E E  98a A A A E E  98bC B E E  99 B B A E E  99a C B E E  99b D C E E 100 C B E E 101 C C E E102 C C E B 102a B B E E A 102b B B E E 103 B B E E 104 B C E D 105 B AE A 106 A B A E E 107 B B D A 107a A A E A 107b B D B A 108 D C E E 109A E A A 110 A B E E A 111 C B E E 112 B B E E B 113 B B E E 114 A A E E115 C C E E 116 D C E E 117 D C E E 118 B B E A 119 C C E E 120 D E E C121 C E B A 122 B B E E A 123 A B B E E 124 B A E E 125 C E E D B 126 AA E E 127 C E B A 128 C B E C 129 E E E E 130 D E C B 131 C E B A 132 DC E E 133 B B E E 134 D C E E 135 A A A E E 136 B A E E 137 A A A E E138 B B E E 139 C C E E 140 D B E C A 140a D E E B 140b B E B A 141 B BE C 142 E E B A 142a E E A A 142b E E C B 143 D E E D 144 B C B E E 145D B E E 146 B E B B 147 E E A A 148 E E E D 149 C E B A 150 E E B A 151E E B A 152 D D E D 153 C C E E 154 D B E E 155 C C E E 156 E E B A 157B B B E B 158 C B E B 159 B C E A 160 C B E E 161 D E B A 162 B A E C163 E E C A 164 D D E E B 165 C E D C 166 C C E C 167 C C E C 168 C C EE 169 C B E E 170 E E E E 171 E E E B 172 E E E C 173 E E C B 174 E E BA 175 A E B A 176 B A E E 177 C C E E 178 A A E E 178a B A E E 178b B AE D 179 C B E E 180 C E E A 181 C A E E 182 E E B A 183 C E C B 184 D EE C 185 D E E C 186 C B C B 187 C C E B 188 B C E B 189 C C E C 190 C BE B 191 C B E E 192 C B E C 193 C E C A 194 C E B A 195 E E E E 196 D CE E 197 B A E E 198 A A E E 199 C E E B 200 C B E B 201 C B E E 202 B BE A 202a D C E B 202b C B B E B 203 B C E A 203a B C E A 203b D D E E204 C B E B 204a C C E E 204b B C B E A 205 B B E B A 206 B A E A A 207C E C C 208 B A E B A 209 B A E E A 210 B B E B A 211 A A A E E 212 B EC A 213 E E E C 214 C C E C 215 C D C C 216 D E E E 216a C C E E 216b DE E D 217 C C E B 219 B B E E 220 B B E B 300 D E E B 301 C B E E 302 AA E E 303 D E E B TABLE 1: (A = <0.1 μM, B = 0.1-1.0 μM, C = 1.0-10.0μM, D = 10.0-30.0 μM, E = >30 μM)

Aripiprazole is of the formula

Clozapine is of the formula:

Cariprazine is of the formula:

UNC9994 is of the formula:

UNC9975 is of the formula

D,L-Stepholidine is of the formula

Quinpirole is of the formula

Dopamine is of the formula: HO

Apomorphine is of the formula

MLS 1547 is of the formula

Compound 300 is of the formula

Compound 301 is of the formula

Compound 302 is of the formula

Compound 303 is of the formula

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will be readily apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations not departing from the spirit or scope ofthe present invention are intended to be embraced by this application.

1. A compound of Formula I

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X⁰ isC₁-C₆ alkyl, X-Cy¹, C(O)NR⁴R^(4′), NR⁴C(O)R^(4′), orCR³R^(3′)—NR⁴R^(4′), and is bonded to Z¹ or Z²; X is C(O), CR³R^(3′),NR⁴, O, S, S(O), or S(O)₂, and is bonded to Z¹ or Z², or Z²-Z¹—X form a4- to 7-membered heterocyclyl ring optionally substituted with one ormore R¹⁸, wherein the heterocyclyl ring, ring G, and Cy¹ form athree-ring fused ring structure, provided that R¹ is not optionallysubstituted phenyl, 2-furyl or 3-furyl, or X—Z¹—R¹ form a 3- to7-membered cycloalkyl or heterocyclyl ring optionally substituted withone or more R¹⁸, wherein the cycloalkyl or heterocyclyl ring is bondedto Cy¹, or the cycloalkyl or heterocyclyl ring and Cy¹ form a fused ringstructure when n is 0 and v is 1 or 3, or X—Z²—R² form a 3- to7-membered cycloalkyl or heterocyclyl ring optionally substituted withone or more R¹⁸, wherein the cycloalkyl or heterocyclyl ring is bondedto Cy¹, or the cycloalkyl or heterocyclyl ring and Cy¹ form a fused ringstructure; R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen; each R⁴ isindependently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(4′) is H, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl, heterocyclyl comprising one 4-to 7-membered ring and one to four heteroatoms independently selectedfrom N, O, and S, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroarylare independently optionally substituted with one or more R¹⁷; or R⁴ andR^(4′) on the same nitrogen atom together with the nitrogen atom form amonocyclic, 4- to 7-membered heterocyclyl ring optionally substitutedwith one or more R¹⁸; Z¹ is CR⁷, or Z²-Z¹—X form a 4- to 7-memberedheterocyclyl ring optionally substituted with one or more R¹⁸, whereinthe heterocyclyl ring, ring G, and Cy¹ form a three-ring fused ringstructure, provided that R¹ is not optionally substituted phenyl,2-furyl or 3-furyl, or X—Z¹—R¹ form a 3- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁸, whereinthe cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the cycloalkylor heterocyclyl ring and Cy¹ form a fused ring structure when n is 0 andv is 1 or 3; R⁷ is H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, or whenX⁰ or X is bonded to Z¹, absent; R¹ is H, halogen, OH, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsindependently selected from N, O, and S, C₃-C₆ cycloalkyl, orheterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, provided that whenX⁰ or X forms a bond with Z¹, R¹ is not H and provided that when X isbonded to Z¹ and is NR⁴, O, S, S(O), or S(O)₂, R¹ is not OH, C₁-C₆alkoxy, NR²⁰R²¹, C₁-C₆ haloalkoxy, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹,or NR²⁰S(O)₂—C₁-C₆ alkyl; or X—Z¹—R¹ form a 3- to 7-membered cycloalkylor heterocyclyl ring optionally substituted with one or more R¹⁸,wherein the cycloalkyl or heterocyclyl ring is bonded to Cy¹, or thecycloalkyl or heterocyclyl ring and Cy¹ form a fused ring structure whenn is 0 and v is 1 or 3, wherein the aryl, benzyl, heteroaryl,cycloalkyl, and heterocyclyl are independently optionally substitutedwith one or more substituents independently selected from halogen, C₁-C₆alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy; Z² is CR⁸,or Z²-Z¹—X form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁸, wherein the heterocyclyl ring, ring G,and Cy¹ form a three-ring fused ring structure, provided that R¹ is notoptionally substituted phenyl, 2-furyl or 3-furyl, or X—Z²—R² form a 3-to 7-membered cycloalkyl or heterocyclyl ring optionally substitutedwith one or more R¹⁸, wherein the cycloalkyl or heterocyclyl ring isbonded to Cy¹, or the cycloalkyl or heterocyclyl ring and Cy¹ form afused ring structure; R⁸ is H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl,or when X⁰ or X is bonded to Z², absent; R² is H, halogen, OH, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, NR²⁰R²¹,C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl,C₆-C₁₀ aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring andone to four heteroatoms independently selected from N, O, and S, C₃-C₆cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and oneto four heteroatoms independently selected from N, O, and S, providedthat when X⁰ or X forms a bond with Z², R² is not H and provided thatwhen X is bonded to Z² and is NR⁴, O, S, S(O), or S(O)₂, R² is not OH,C₁-C₆ alkoxy, NR²⁰R²¹, C₁-C₆ haloalkoxy, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl; or X—Z²—R² form a 3- to7-membered cycloalkyl or heterocyclyl ring optionally substituted withone or more R¹⁸, wherein the cycloalkyl or heterocyclyl ring is bondedto Cy¹, or the cycloalkyl or heterocyclyl ring and Cy¹ form a fused ringstructure, wherein the aryl, benzyl, heteroaryl, cycloalkyl, andheterocyclyl are independently optionally substituted with one or moresubstituents independently selected from halogen, C₁-C₆ alkyl, OH,C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy; each R¹⁸ isindependently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, orC₁-C₆ haloalkoxy; or two R¹⁸ together with the carbon atom to which theyare bonded form a C(O); q is 0, 1, or 2; R²⁰ and R²¹ are eachindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₆-C₁₀ aryl, whereinthe aryl is optionally substituted with one or more substituentsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, and halogen; Cy¹ is C₆-C₁₀ aryl, benzyl, or heteroarylcomprising one or two 5- or 6-membered rings and one to four heteroatomsindependently selected from N, O, and S, wherein each ring is aromaticor partially unsaturated, or N—(C₆-C₁₀ aryl) when X is CR³R^(3′) andwhen X—Z¹—R¹ form a 3- to 7-membered heterocyclyl ring, wherein thearyl, benzyl, and heteroaryl are independently optionally substitutedwith one or more R¹⁶, provided that when p is 1, X is NH and is bondedto Z¹, and R¹ is C(O)NH₂, then Cy¹ is not unsubstituted phenyl, when pis 1, X is CH₂ and is bonded to Z¹, and R¹ is OH or halogen, then Cy¹ isnot optionally substituted phenyl, benzoimidazolyl, benzoimidazolonyl,or dihydroquinoxaline-2,3-dione; and when p is 1, X is C(O) and isbonded to Z¹, Y is O, and R¹ is OH or methoxy, then Cy¹ is notoptionally substituted phenyl; each R¹⁶ is independently halogen, C₁-C₆alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃alkyl), S(O)_(q)—(C₁-C₃) alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl,or NO₂; Z³ is C(R⁹)₂; each R⁹ is independently H, halogen, C₁-C₆ alkyl,or C₁-C₆ haloalkyl; p is 0 or 1; Z′ is C(R¹²)₂; or Z′ and Z³ togetherwith the atom(s) to which they are bonded form a 4- to 7-memberedcycloalkyl or heterocyclyl ring which, together with ring G, forms afused ring structure; or Z′ and Z³ together with the atom(s) to whichthey are bonded form a 4- to 7-membered aryl or heteroaryl ring which,together with ring G, forms a fused ring structure; Z″ is C(R¹³)₂; or Z″and Z² together with the atom(s) to which they are bonded form a 4- to7-membered cycloalkyl or heterocyclyl ring which, together with ring G,forms a fused ring structure; or Z″ and Z² together with the atom(s) towhich they are bonded form a 4- to 7-membered aryl or heteroaryl ringwhich, together with ring G, forms a fused ring structure; each R¹² isindependently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or halogen, or two R¹²together with the carbon atom to which they are bonded form a 3- to6-membered cycloalkyl or heterocyclyl ring which, together with ring G,forms a spirocyclic ring structure; each R¹³ is independently H, C₁-C₃alkyl, C₁-C₃ haloalkyl, or halogen, or two R¹³ together with the carbonatom to which they are bonded form a 3- to 6-membered cycloalkyl orheterocyclyl ring which, together with ring G, forms a spirocyclic ringstructure; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴ isindependently H or C₁-C₃ alkyl; Z⁴ is when n is 0 or 1, C(R¹⁰)₂, or whenn is 0, Y—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl or heterocyclyl ringoptionally substituted with one or more R¹⁹; each R¹⁷ is independentlyhalogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or two R¹⁷ together with the carbonatoms to which they are bonded form a C₆-C₁₀ aryl or heteroaryloptionally substituted with one or more R¹⁹, or when n is 0, Y—Z⁴—R¹⁷form a 4- to 7-membered heterocyclyl ring optionally substituted withone or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; each R¹⁰ is independentlyH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰ together withthe carbon atom to which they are bonded, form C(O); Y is when n is 0 or1, C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or when n is 0 or 1,Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ring optionally substitutedwith one or more R¹⁹, or when n is 0, Y—Z⁴—R¹⁷ form a 4- to 7-memberedheterocyclyl ring optionally substituted with one or more R¹⁹, or when nis 0 and Cy² is absent, pyridinonyl optionally substituted with one ormore R¹⁷; R⁵ and R^(5′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen; R⁶ is H, C₁-C₆alkyl, or C₁-C₆ haloalkyl; Z⁵ is C(R¹¹)₂; each R¹¹ is independently H,C₁-C₆ alkyl, C₁-C₆haloalkyl, or halogen; n is 0 or 1; Cy² is C₃-C₈cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one tofour heteroatoms independently selected from N, O, and S, C₆-C₁₀ aryl,or heteroaryl comprising one or two 5- or 6-membered rings and one tofour heteroatoms independently selected from N, O, and S, or absent whenn is 0 and Y is pyridinonyl, wherein the cycloalkyl, heterocyclyl, aryl,and heteroaryl are independently optionally substituted with one or moreR¹⁷; and provided that a compound of Formula (I) is not1-(methylsulfonyl)-5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile;or5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile.2. The compound of claim 1, or a stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptablesalt thereof, wherein: X⁰ is C₁-C₆ alkyl or X-Cy¹, and is bonded to Z¹or Z²; X is C(O), CR³R^(3′), NR⁴, O, S, S(O), or S(O)₂, and is bonded toZ¹ or Z², or Z²-Z¹—X form a 4- to 7-membered heterocyclyl ringoptionally substituted with one or more R¹⁸, wherein the heterocyclylring, ring G, and Cy¹ form a three-ring fused ring structure, providedthat R¹ is not optionally substituted phenyl, 2-furyl or 3-furyl, orX—Z¹—R¹ form a 3- to 7-membered cycloalkyl or heterocyclyl ringoptionally substituted with one or more R¹⁸, wherein the cycloalkyl orheterocyclyl ring is bonded to Cy¹, or the cycloalkyl or heterocyclylring and Cy¹ form a fused ring structure when n is 0 and v is 1 or 3, orX—Z²—R² form a 3- to 7-membered cycloalkyl or heterocyclyl ringoptionally substituted with one or more R¹⁸, wherein the cycloalkyl orheterocyclyl ring is bonded to Cy¹, or the cycloalkyl or heterocyclylring and Cy¹ form a fused ring structure; R³ and R^(3′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; Z¹ isCR⁷, or Z²-Z¹—X form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁸, wherein the heterocyclyl ring, ring G,and Cy¹ form a three-ring fused ring structure, provided that R¹ is notoptionally substituted phenyl, 2-furyl or 3-furyl, or X—Z¹—R¹ form a 3-to 7-membered cycloalkyl or heterocyclyl ring optionally substitutedwith one or more R¹⁸, wherein the cycloalkyl or heterocyclyl ring isbonded to Cy¹, or the cycloalkyl or heterocyclyl ring and Cy¹ form afused ring structure when n is 0 and v is 1 or 3; R⁷ is H, halogen,C₁-C₆ alkyl, or C₁-C₆ haloalkyl, or when X⁰ or X is bonded to Z¹,absent; R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsselected from N, O, and S, C₃-C₆ cycloalkyl, or heterocyclyl comprisingone 4- to 6-membered ring and one to four heteroatoms selected from N,O, and S, provided that when X⁰ or X forms a bond with Z¹, R¹ is not Hand provided that when X is bonded to Z¹ and is NR⁴, O, S, S(O), orS(O)₂, R¹ is not OH, C₁-C₆ alkoxy, NR²⁰R²¹, C₁-C₆ haloalkoxy,S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl; or X—Z¹—R¹form a 3- to 7-membered cycloalkyl or heterocyclyl ring optionallysubstituted with one or more R¹⁸, wherein the cycloalkyl or heterocyclylring is bonded to Cy¹, or the cycloalkyl or heterocyclyl ring and Cy¹form a fused ring structure when n is 0 and v is 1 or 3, wherein thearyl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents independently selected fromhalogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆haloalkoxy; Z² is CR⁸, or Z²-Z¹—X form a 4- to 7-membered heterocyclylring optionally substituted with one or more R¹⁸, wherein theheterocyclyl ring, ring G, and Cy¹ form a three-ring fused ringstructure, provided that R¹ is not optionally substituted phenyl,2-furyl or 3-furyl, or X—Z²—R² form a 3- to 7-membered cycloalkyl orheterocyclyl ring optionally substituted with one or more R¹⁸, whereinthe cycloalkyl or heterocyclyl ring is bonded to Cy¹, or the cycloalkylor heterocyclyl ring and Cy¹ form a fused ring structure; R⁸ is H,halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, or when X⁰ or X is bonded toZ², absent; R² is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsselected from N, O, and S, C₃-C₆ cycloalkyl, or heterocyclyl comprisingone 4- to 6-membered ring and one to four heteroatoms selected from N,O, and S, provided that when X⁰ or X forms a bond with Z², R² is not Hand provided that when X is bonded to Z² and is NR⁴, O, S, S(O), orS(O)₂, R² is not OH, C₁-C₆alkoxy, NR²⁰R²¹, C₁-C₆ haloalkoxy,S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆ alkyl; or X—Z²—R²form a 3- to 7-membered cycloalkyl or heterocyclyl ring optionallysubstituted with one or more R¹⁸, wherein the cycloalkyl or heterocyclylring is bonded to Cy¹, or the cycloalkyl or heterocyclyl ring and Cy¹form a fused ring structure, wherein the aryl, benzyl, heteroaryl,cycloalkyl, and heterocyclyl are optionally substituted with one or moresubstituents independently selected from halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy; each R¹⁸ is independentlyhalogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, or C₁-C₆haloalkoxy; or two R¹⁸ together with the carbon atom to which they arebonded form a C(O); q is 0, 1, or 2; R²⁰ and R²¹ are each independentlyH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₆-C₁₀ aryl, wherein the aryl isoptionally substituted with one or more substituents selected from C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, and halogen; Cy¹is C₆-C₁₀ aryl, benzyl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms selected from N, O, and Swherein each ring is aromatic or partially unsaturated, or N—(C₆-C₁₀aryl) when X is CR³R^(3′) and when X—Z¹—R¹ form a 3- to 7-memberedheterocyclyl ring, wherein the aryl, benzyl, and heteroaryl areoptionally substituted with one or more R¹⁶, provided that when p is 1,X is NH and is bonded to Z¹, and R¹ is C(O)NH₂, then Cy¹ is notunsubstituted phenyl, when p is 1, X is CH₂ and is bonded to Z¹, and R¹is OH or halogen, then Cy¹ is not optionally substituted phenyl,benzoimidazolyl, benzoimidazolonyl, or dihydroquinoxaline-2,3-dione; andwhen p is 1, X is C(O) and is bonded to Z¹, Y is O, and R¹ is OH ormethoxy, then Cy¹ is not optionally substituted phenyl; each R¹⁶ isindependently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl, NH₂,N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; Z³ is C(R⁹)₂; each R⁹ isindependently H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; p is 0 or 1;Z′ is C(R¹²)₂; or Z′ and Z³ together with the atom(s) to which they arebonded form a 4- to 7-membered cycloalkyl or heterocyclyl ring which,together with ring G, forms a fused ring structure; or Z′ and Z³together with the atom(s) to which they are bonded form a 4- to7-membered aryl or heteroaryl ring which, together with ring G, forms afused ring structure; Z″ is C(R¹³)₂; or Z″ and Z² together with theatom(s) to which they are bonded form a 4- to 7-membered cycloalkyl orheterocyclyl ring which, together with ring G, forms a fused ringstructure; or Z″ and Z² together with the atom(s) to which they arebonded form a 4- to 7-membered aryl or heteroaryl ring which, togetherwith ring G, forms a fused ring structure; each R¹² is independently H,C₁-C₃ alkyl, C₁-C₃ haloalkyl, or halogen, or two R¹² together with thecarbon atom to which they are bonded form a 3- to 6-membered cycloalkylor heterocyclyl ring which, together with ring G, forms a spirocyclicring structure; each R¹³ is independently H, C₁-C₃ alkyl, C₁-C₃haloalkyl, or halogen, or two R¹³ together with the carbon atom to whichthey are bonded form a 3- to 6-membered cycloalkyl or heterocyclyl ringwhich, together with ring G, forms a spirocyclic ring structure; or R¹²and R¹³, together with the carbon atoms to which they are bonded and thenitrogen atom in ring G, form a 5- to 7-membered heterocyclyl ring,wherein the heterocyclyl ring and ring G form a bridged ring structure;Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴ is independently H or C₁-C₃alkyl; Z⁴ is when n is 0 or 1, C(R¹⁰)₂, or when n is 0, Y—Z⁴—R¹⁷ form a4- to 7-membered cycloalkyl or heterocyclyl ring optionally substitutedwith one or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl,OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or when n is 0, Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ringoptionally substituted with one or more R¹⁹; each R¹⁹ is independentlyC₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen;each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen;or two R¹⁰ together with the carbon atom to which they are bonded, formC(O); Y is when n is 0 or 1, C(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂,or when n is 0 or 1, Y—Z⁴-Z⁶ form a 4- to 7-membered heterocyclyl ringoptionally substituted with one or more R¹⁹, or when n is 0, Y—Z⁴—R¹⁷form a 4- to 7-membered heterocyclyl ring optionally substituted withone or more R¹⁹, or when n is 0 and Cy² is absent, pyridinonyloptionally substituted with one or more R¹⁷; R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; Z⁵ isC(R¹¹)₂; each R¹¹ is independently H, C₁-C₆ alkyl, C₁-C₆haloalkyl, orhalogen; n is 0 or 1; Cy² is C₃-C₈ cycloalkyl, heterocyclyl comprisingone 4- to 7-membered ring and one to four heteroatoms selected from N,O, and S, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms selected from N, O, and S,or absent when n is 0 and Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are optionally substituted with oneor more R¹⁷; and provided that a compound of Formula (I) is not1-(methylsulfonyl)-5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile;or5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile.3. (canceled)
 4. The compound of claim 1, having Formula (II)

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X⁰ isC₁-C₆ alkyl, X-Cy¹, C(O)NR⁴R^(4′), NR⁴C(O)R^(4′), orCR³R^(3′)—NR⁴R^(4′;) X is C(O), CR³R^(3′), NR⁴, O, S, S(O), or S(O)₂; R³and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen; R⁴ is H, C₁-C₆ alkyl, orC₁-C₆ haloalkyl; R¹ is halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsindependently selected from N, O, and S, C₃-C₆ cycloalkyl, orheterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, provided that whenX is NR⁴, O, S, S(O), or S(O)₂, R¹ is not OH, C₁-C₆ alkoxy, NR²⁰R²¹,C₁-C₆haloalkoxy, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆alkyl, wherein the aryl, benzyl, heteroaryl, cycloalkyl, andheterocyclyl are independently optionally substituted with one or moresubstituents independently selected from halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy; q is 0, 1, or 2; R²⁰ andR²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₆-C₁₀aryl, wherein the aryl is optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and halogen; Cy¹ is C₆-C₁₀ aryl,benzyl, or heteroaryl comprising one or two 5- or 6-membered rings andone to four heteroatoms independently selected from N, O, and S, whereineach ring is aromatic or partially unsaturated, wherein the aryl,benzyl, and heteroaryl are independently optionally substituted with oneor more R¹⁶, provided that when X is NH and R¹ is C(O)NH₂, then Cy¹ isnot unsubstituted phenyl, when X is CH₂ and R¹ is OH or halogen, thenCy¹ is not optionally substituted phenyl, benzoimidazolyl,benzoimidazolonyl, or dihydroquinoxaline-2,3-dione; and when X is C(O),Y is O, and R¹ is OH or methoxy, then Cy¹ is not optionally substitutedphenyl; each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl),S(O)_(q)—(C₁-C₃) alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen, or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴ isindependently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to7-membered cycloalkyl or heterocyclyl ring optionally substituted withone or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹, or when Cy² is absent, pyridinonyloptionally substituted with one more R¹⁷, or R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; andCy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.
 5. The compound of claim 1, havingFormula (III)

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X⁰ isC₁-C₆ alkyl or X-Cy¹; X is C(O), CR³R^(3′), NR⁴, O, S, S(O), or S(O)₂;R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen; R⁴ is H, C₁-C₆ alkyl, orC₁-C₆ haloalkyl; R² is halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsindependently selected from N, O, and S, C₃-C₆ cycloalkyl, orheterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, provided that whenX is NR⁴, O, S, S(O), or S(O)₂, R² is not OH, C₁-C₆ alkoxy, NR²⁰R²¹,C₁-C₆haloalkoxy, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆alkyl, wherein the aryl, benzyl, heteroaryl, cycloalkyl, andheterocyclyl are independently optionally substituted with one or moresubstituents independently selected from halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy; q is 0, 1, or 2; R²⁰ andR²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₆-C₁₀aryl, wherein the aryl is optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and halogen; Cy¹ is C₆-C₁₀ aryl,benzyl, or heteroaryl comprising one or two 5- or 6-membered rings andone to four heteroatoms independently selected from N, O, and S, whereineach ring is aromatic or partially unsaturated, wherein the aryl,benzyl, and heteroaryl are independently optionally substituted with oneor more R¹⁶; each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl),S(O)_(q)—(C₁-C₃) alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴ isindependently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to7-membered cycloalkyl or heterocyclyl ring optionally substituted withone or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹, or when Cy² is absent, pyridinonyloptionally substituted with one more R¹⁷; R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; andCy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.
 6. The compound of claim 1, havingFormula (IV)

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X⁰ isC₁-C₆ alkyl or X-Cy¹; X is C(O), CR³R^(3′), NR⁴, O, S, S(O), or S(O)₂;R³ and R^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen; R⁴ is H, C₁-C₆ alkyl, orC₁-C₆ haloalkyl; R² is halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsindependently selected from N, O, and S, C₃-C₆ cycloalkyl, orheterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, provided that whenX is NR⁴, O, S, S(O), or S(O)₂, R² is not OH, C₁-C₆ alkoxy, NR²⁰R²¹,C₁-C₆haloalkoxy, S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, or NR²⁰S(O)₂—C₁-C₆alkyl, wherein the aryl, benzyl, heteroaryl, cycloalkyl, andheterocyclyl are independently optionally substituted with one or moresubstituents independently selected from halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy; q is 0, 1, or 2; R²⁰ andR²¹ are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₆-C₁₀aryl, wherein the aryl is optionally substituted with one or moresubstituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, and halogen; Cy¹ is C₆-C₁₀ aryl,benzyl, or heteroaryl comprising one or two 5- or 6-membered rings andone to four heteroatoms independently selected from N, O, and S, whereineach ring is aromatic or partially unsaturated, wherein the aryl,benzyl, and heteroaryl are independently optionally substituted with oneor more R¹⁶; each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl),S(O)_(q)—(C₁-C₃) alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂;R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴ isindependently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to7-membered cycloalkyl or heterocyclyl ring optionally substituted withone or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹, or when Cy² is absent, pyridinonyloptionally substituted with one more R¹⁷; R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; andCy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.
 7. The compound of claim 1, havingformula (V):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X isCR³ or N; R³ is H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, orC₁-C₆ haloalkoxy; each K is independently NR²², C(O), O, or CR²²R²³;each R²² and R²³ is independently H, OH, C₁-C₆ alkyl, or C₆-C₁₀ aryl,wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, and C₁-C₆ haloalkoxy; Cy¹ is C₆-C₁₀ aryl, benzyl, orheteroaryl comprising one or two 5- or 6-membered rings and one to fourheteroatoms independently selected from N, O, and S, wherein each ringis aromatic or partially unsaturated, wherein the aryl, benzyl, andheteroaryl are independently optionally substituted with one or moreR¹⁶; each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃)alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; q is 0, 1, or 2; wis 1, 2, 3, or 4; p is 0 or 1; R¹² and R¹³ are each independently H,C₁-C₃ alkyl, C₁-C₃ haloalkyl, or halogen; or R¹² and R¹³, together withthe carbon atoms to which they are bonded and the nitrogen atom in ringG, form a 5- to 7-membered heterocyclyl ring, wherein the heterocyclylring and ring G form a bridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2,or 3; each R¹⁴ is independently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, orY—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl or heterocyclyl ringoptionally substituted with one or more R¹⁹; each R¹⁷ is independentlyhalogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or two R¹⁷ together with the carbonatoms to which they are bonded form a C₆-C₁₀ aryl or heteroaryloptionally substituted with one or more R¹⁹, or Y—Z⁴—R¹⁷ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹; each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, or halogen; each R¹⁰ is independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰ together with thecarbon atom to which they are bonded, form C(O); Y is C(O), CR⁵R^(5′),NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to 7-memberedheterocyclyl ring optionally substituted with one or more R¹⁹, orY—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹, or when Cy² is absent, pyridinonyloptionally substituted with one or more R¹⁷; R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; Cy² isC₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring andone to four heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl, or heteroaryl comprising one or two 5- or 6-membered rings and oneto four heteroatoms independently selected from N, O, and S, or absentwhen Y is pyridinonyl, wherein the cycloalkyl, heterocyclyl, aryl, andheteroaryl are independently optionally substituted with one or moreR¹⁷; and provided that a compound of Formula (V) is not1-(methylsulfonyl)-5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile;or5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile.8. The compound of claim 1, having formula (VI)

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X isCR³ or N; R³ is H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, orC₁-C₆ haloalkoxy; each K is independently NR²², C(O), O, or CR²²R²³;each R²² and R₂₃ is independently H, OH, C₁-C₆ alkyl, or C₆-C₁₀ aryl,wherein the aryl is optionally substituted with one or more substituentsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, and C₁-C₆ haloalkoxy; Cy¹ is C₆-C₁₀ aryl, benzyl, orheteroaryl comprising one or two 5- or 6-membered rings and one to fourheteroatoms independently selected from N, O, and S, wherein each ringis aromatic or partially unsaturated, wherein the aryl, benzyl, andheteroaryl are independently optionally substituted with one or moreR¹⁶; each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃)alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; q is 0, 1, or 2; wis 1, 2, 3, or 4; p is 0 or 1; R¹² and R¹³ are each independently H,C₁-C₃ alkyl, C₁-C₃ haloalkyl, or halogen; or R¹² and R¹³, together withthe carbon atoms to which they are bonded and the nitrogen atom in ringG, form a 5- to 7-membered heterocyclyl ring, wherein the heterocyclylring and ring G form a bridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2,or 3; each R¹⁴ is independently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, orY—Z⁴—R¹⁷ form a 4- to 7-membered cycloalkyl or heterocyclyl ringoptionally substituted with one or more R¹⁹; each R¹⁷ is independentlyhalogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C(O)—C₁-C₃ alkyl, S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; or two R¹⁷ together with the carbonatoms to which they are bonded form a C₆-C₁₀ aryl or heteroaryloptionally substituted with one or more R¹⁹, or Y—Z⁴—R¹⁷ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹; each R¹⁹ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, or halogen; each R¹⁰ is independently H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰ together with thecarbon atom to which they are bonded, form C(O); Y is C(O), CR⁵R^(5′),NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to 7-memberedheterocyclyl ring optionally substituted with one or more R¹⁹, orY—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹, or when Cy² is absent, pyridinonyloptionally substituted with one or more R¹⁷; R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; andCy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.
 9. The compound of claim 1, havingformula (VII)

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X isCR³R^(3′), NR⁴, or O; R³ and R^(3′) are each independently H, C₁-C₆alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; each R¹⁶ is independentlyhalogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl, NH₂, N(C₁-C₆alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; q is 0, 1, or 2; h is 1, 2, or 3; g is0, 1, 2, 3, or 4; p is 0 or 1; each R²⁴ and R²⁵ are independently H,C₁-C₃ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy, orR²⁴ and R²⁵ together with the carbon atom to which they are bonded formC(O); R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃haloalkyl, or halogen; or R¹² and R¹³, together with the carbon atoms towhich they are bonded and the nitrogen atom in ring G, form a 5- to7-membered heterocyclyl ring, wherein the heterocyclyl ring and ring Gform a bridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴is independently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4-to 7-membered cycloalkyl or heterocyclyl ring optionally substitutedwith one or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl,OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹, or when Cy² is absent, pyridinonyloptionally substituted with one or more R¹⁷; R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; andCy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.
 10. The compound of claim 1, havingformula (VIII)

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X isCR³R^(3′), NR⁴, or O; R³ and R^(3′) are each independently H, C₁-C₆alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; each R¹⁶ is independentlyhalogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, C(O)—(C₁-C₃ alkyl), S(O)_(q)—(C₁-C₃) alkyl, NH₂, N(C₁-C₆alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; q is 0, 1, or 2; h is 1, 2, or 3; g is0, 1, 2, 3, or 4; p is 0 or 1; each R²⁴ and R²⁵ are independently H,C₁-C₃ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy, orR²⁴ and R²⁵ together with the carbon atom to which they are bonded formC(O); R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃haloalkyl, or halogen; or R¹² and R¹³, together with the carbon atoms towhich they are bonded and the nitrogen atom in ring G, form a 5- to7-membered heterocyclyl ring, wherein the heterocyclyl ring and ring Gform a bridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴is independently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4-to 7-membered cycloalkyl or heterocyclyl ring optionally substitutedwith one or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl,OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹, or when Cy² is absent, pyridinonyloptionally substituted with one or more R¹⁷; R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; andCy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.
 11. The compound of claim 1, havingformula (IX):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X isCR³R^(3′), NR⁴, or O; R³ and R^(3′) are each independently H, C₁-C₆alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R¹ is H, halogen, OH, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy; R² is H,halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆haloalkoxy, provided that when X is NR⁴ or O, R² is not OH, C₁-C₆alkoxy, or C₁-C₆haloalkoxy; each R¹⁶ is independently halogen, C₁-C₆alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃alkyl), S(O)_(q)—(C₁-C₃) alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl,or NO₂; q is 0, 1, or 2; i is 0, 1, or 2; g is 0, 1, 2, 3, or 4; p is 0or 1; R¹² and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃haloalkyl, or halogen; or R¹² and R¹³, together with the carbon atoms towhich they are bonded and the nitrogen atom in ring G, form a 5- to7-membered heterocyclyl ring, wherein the heterocyclyl ring and ring Gform a bridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴is independently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4-to 7-membered cycloalkyl or heterocyclyl ring optionally substitutedwith one or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl,OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹, or when Cy² is absent, pyridinonyloptionally substituted with one or more R¹⁷; R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; andCy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.
 12. The compound of claim 1, havingformula (X)

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: X isCR³R^(3′), NR⁴, or O; R³ and R^(3′) are each independently H, C₁-C₆alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen;R⁴ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R¹ is H, halogen, OH, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy, provided thatwhen X is NR⁴ or O, R¹ is not OH, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy; R²is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆haloalkoxy; each R¹⁶ is independently halogen, C₁-C₆ alkyl, OH,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—(C₁-C₃ alkyl),S(O)_(q)—(C₁-C₃) alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; qis 0, 1, or 2; i is 0, 1, or 2; g is 0, 1, 2, 3, or 4; p is 0 or 1; R¹²and R¹³ are each independently H, C₁-C₃ alkyl, C₁-C₃ haloalkyl, orhalogen; or R¹² and R¹³, together with the carbon atoms to which theyare bonded and the nitrogen atom in ring G, form a 5- to 7-memberedheterocyclyl ring, wherein the heterocyclyl ring and ring G form abridged ring structure; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴ isindependently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4- to7-membered cycloalkyl or heterocyclyl ring optionally substituted withone or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl, OH,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹, or when Cy² is absent, pyridinonyloptionally substituted with one or more R¹⁷; R⁵ and R^(5′) are eachindependently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; andCy² is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to 7-memberedring and one to four heteroatoms independently selected from N, O, andS, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or 6-memberedrings and one to four heteroatoms independently selected from N, O, andS, or absent when Y is pyridinonyl, wherein the cycloalkyl,heterocyclyl, aryl, and heteroaryl are independently optionallysubstituted with one or more R¹⁷.
 13. The compound of claim 1, havingformula (XI)

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: R⁴ isH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(4′) is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to7-membered ring and one to four heteroatoms independently selected fromN, O, and S, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroarylare independently optionally substituted with one or more R¹⁷; or R⁴ andR^(4′) on the same nitrogen atom together with the nitrogen atom form amonocyclic, 4- to 7-membered heterocyclyl ring optionally substitutedwith one or more R¹⁸; R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹,S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl,benzyl, heteroaryl comprising one 5- or 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, C₃-C₆ cycloalkyl,or heterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, wherein the aryl,benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independentlyoptionally substituted with one or more substituents independentlyselected from halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,and C₁-C₆ haloalkoxy; each q is independently 0, 1, or 2; R²⁰ and R²¹are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₆-C₁₀ aryl,wherein the aryl is optionally substituted with one or more substituentsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, and halogen; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴is independently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4-to 7-membered cycloalkyl or heterocyclyl ring optionally substitutedwith one or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl,OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; R⁵ and R^(5′) are each independentlyH, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, orhalogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; Cy² is C₃-C₈cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one tofour heteroatoms independently selected from N, O, and S, C₆-C₁₀ aryl,or heteroaryl comprising one or two 5- or 6-membered rings and one tofour heteroatoms independently selected from N, O, and S, wherein thecycloalkyl, heterocyclyl, aryl, and heteroaryl are independentlyoptionally substituted with one or more R¹⁷; each R³⁰ is independentlyhalogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; and r is 0, 1, 2, 3, or
 4. 14.The compound of claim 1, having formula (XII)

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: R⁴ isH, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(4′) is H, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to7-membered ring and one to four heteroatoms independently selected fromN, O, and S, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or6-membered rings and one to four heteroatoms independently selected fromN, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroarylare independently optionally substituted with one or more R¹⁷; or R⁴ andR^(4′) on the same nitrogen atom together with the nitrogen atom form amonocyclic, 4- to 7-membered heterocyclyl ring optionally substitutedwith one or more R¹⁸; R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹,S(O)_(q)—C₁-C₆ alkyl, S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl,benzyl, heteroaryl comprising one 5- or 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, C₃-C₆ cycloalkyl,or heterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, wherein the aryl,benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independentlyoptionally substituted with one or more substituents independentlyselected from halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl,and C₁-C₆ haloalkoxy; each q is independently 0, 1, or 2; R²⁰ and R²¹are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₆-C₁₀ aryl,wherein the aryl is optionally substituted with one or more substituentsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, and halogen; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴is independently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4-to 7-membered cycloalkyl or heterocyclyl ring optionally substitutedwith one or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl,OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; R⁵ and R^(5′) are each independentlyH, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, orhalogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; Cy² is C₃-C₈cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one tofour heteroatoms independently selected from N, O, and S, C₆-C₁₀ aryl,or heteroaryl comprising one or two 5- or 6-membered rings and one tofour heteroatoms independently selected from N, O, and S, wherein thecycloalkyl, heterocyclyl, aryl, and heteroaryl are independentlyoptionally substituted with one or more R¹⁷; each R³⁰ is independentlyhalogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; and r is 0, 1, 2, 3, or
 4. 15.The compound of claim 1, having formula (XIII):

or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvatethereof, or a pharmaceutically acceptable salt thereof, wherein: R³ andR^(3′) are each independently H, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, or halogen; R⁴ is H, C₁-C₆ alkyl, or C₁-C₆haloalkyl; R^(4′) is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl,heterocyclyl comprising one 4- to 7-membered ring and one to fourheteroatoms independently selected from N, O, and S, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and one to fourheteroatoms independently selected from N, O, and S, wherein thecycloalkyl, heterocyclyl, aryl, and heteroaryl are independentlyoptionally substituted with one or more R¹⁷; or R⁴ and R^(4′) on thesame nitrogen atom together with the nitrogen atom form a monocyclic, 4-to 7-membered heterocyclyl ring optionally substituted with one or moreR¹⁸; R¹ is H, halogen, OH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆haloalkoxy, NR²⁰R²¹, C(O)NR²⁰R²¹, S(O)_(q)—C₁-C₆ alkyl,S(O)₂NR²⁰R²¹, NR²⁰S(O)₂—C₁-C₆ alkyl, C₆-C₁₀ aryl, benzyl, heteroarylcomprising one 5- or 6-membered ring and one to four heteroatomsindependently selected from N, O, and S, C₃-C₆ cycloalkyl, orheterocyclyl comprising one 4- to 6-membered ring and one to fourheteroatoms independently selected from N, O, and S, wherein the aryl,benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independentlyoptionally substituted with one or more substituents independentlyselected from halogen, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,and C₁-C₆ haloalkoxy; each q is independently 0, 1, or 2; R²⁰ and R²¹are each independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₆-C₁₀ aryl,wherein the aryl is optionally substituted with one or more substituentsindependently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, and halogen; Z⁶ is C(R¹⁴)₂; v is 1, 2, or 3; each R¹⁴is independently H or C₁-C₃ alkyl; Z⁴ is C(R¹⁰)₂, or Y—Z⁴—R¹⁷ form a 4-to 7-membered cycloalkyl or heterocyclyl ring optionally substitutedwith one or more R¹⁹; each R¹⁷ is independently halogen, C₁-C₆ alkyl,OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C(O)—C₁-C₃ alkyl,S(O)_(q)—C₁-C₃ alkyl, NH₂, N(C₁-C₆ alkyl)₂, CN, C₆-C₁₀ aryl, or NO₂; ortwo R¹⁷ together with the carbon atoms to which they are bonded form aC₆-C₁₀ aryl or heteroaryl optionally substituted with one or more R¹⁹,or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; each R¹⁹ is independently C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or halogen; each R¹⁰ isindependently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or halogen; or two R¹⁰together with the carbon atom to which they are bonded, form C(O); Y isC(O), CR⁵R^(5′), NR⁶, O, S, S(O), or S(O)₂, or Y—Z⁴-Z⁶ form a 4- to7-membered heterocyclyl ring optionally substituted with one or moreR¹⁹, or Y—Z⁴—R¹⁷ form a 4- to 7-membered heterocyclyl ring optionallysubstituted with one or more R¹⁹; R⁵ and R^(5′) are each independentlyH, C₁-C₆ alkyl, OH, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, orhalogen; R⁶ is H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; Cy² is C₃-C₈cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one tofour heteroatoms independently selected from N, O, and S, C₆-C₁₀ aryl,or heteroaryl comprising one or two 5- or 6-membered rings and one tofour heteroatoms independently selected from N, O, and S, wherein thecycloalkyl, heterocyclyl, aryl, and heteroaryl are independentlyoptionally substituted with one or more R¹⁷; each R³⁰ is independentlyhalogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; and r is 0, 1, 2, 3, or 4.16-39. (canceled)
 40. The compound of claim 1, selected from the groupconsisting of:3-(4-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-(4-chlorophenoxy)-1-(2-(2-methoxyphenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(3-methoxyphenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(4-methoxyphenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(3-fluorophenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(4-fluorophenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(2,4-difluorophenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(2,5-difluorophenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(3-chlorophenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(4-chlorophenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(2-(3,4-dichlorophenoxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(2-(o-tolyloxy)ethyl)pyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(2-(m-tolyloxy)ethyl)pyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(2-(p-tolyloxy)ethyl)pyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)pyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(2-(3-(trifluoromethyl)phenoxy)ethyl)pyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)pyrrolidine;1-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethyl)pyridin-2(1H)-one;3-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)pyridine;5-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine;1-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethyl)pyridin-4(1H)-one;3-(4-chlorophenoxy)-1-(2-(cyclohexyloxy)ethyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(2-(naphthalen-1-yloxy)ethyl)pyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(2-(naphthalen-2-yloxy)ethyl)pyrrolidine;6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolone;6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)isoquinoline;7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)isoquinoline;7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolone;7-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)quinolin-2(1H)-one;6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)benzo[d]thiazole;6-(2-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)ethoxy)benzo[d]oxazole;1-(2-([1,1′-biphenyl]-3-yloxy)ethyl)-3-(4-chlorophenoxy)-3-methylpyrrolidine;6-(4-(3-(4-chlorophenoxy)-3-methylpyrrolidin-1-yl)butoxy)benzo[d]thiazole;3-(4-chlorophenoxy)-3-methyl-1-(3-phenoxypropyl)pyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(4-phenoxybutyl)pyrrolidine;3-(4-chlorophenoxy)-1-(4-(2-fluorophenoxy)butyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-1-(4-(2-chlorophenoxy)butyl)-3-methylpyrrolidine;3-(4-chlorophenoxy)-3-methyl-1-(3-phenylpropyl)pyrrolidine;5-chloro-1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine];(3aS,9aR)-7-chloro-2-(2-phenoxyethyl)-1,2,3,3a,9,9a-hexahydrochromeno[2,3-c]pyrrole;4-((1-(2-phenoxyethyl)-3-phenylpyrrolidin-3-yl)oxy)aniline;3-(4-nitrophenoxy)-1-(2-phenoxyethyl)-3-phenylpyrrolidine;3-methyl-3-phenoxy-1-(2-phenoxyethyl)pyrrolidine;3-methyl-3-(2-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine;3-methyl-3-(3-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine;3-methyl-3-(4-nitrophenoxy)-1-(2-phenoxyethyl)pyrrolidine;4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline;3-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline;2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)aniline;3-methyl-1-(2-phenoxyethyl)-3-(o-tolyloxy)pyrrolidine;3-(2-methoxyphenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-(2-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-(3-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-(4-fluorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-(2-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-(3-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-(2,3-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-(3,4-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-(2,4-dichlorophenoxy)-3-methyl-1-(2-phenoxyethyl)pyrrolidine;3-methyl-1-(2-phenoxyethyl)-3-(2-(trifluoromethyl)phenoxy)pyrrolidine;3-methyl-1-(2-phenoxyethyl)-3-(3-(trifluoromethyl)phenoxy)pyrrolidine;3-methyl-1-(2-phenoxyethyl)-3-(4-(trifluoromethyl)phenoxy)pyrrolidine;2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine;3-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine;4-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyridine;2-((3-methyl-1-(2-phenoxyethyl)pyrrolidin-3-yl)oxy)pyrazine;4-(4-chlorophenoxy)-4-methyl-1-(2-phenoxyethyl)piperidine;4-(4-chlorophenoxy)-4-methyl-1-(4-phenoxybutyl)piperidine;4-methyl-4-phenoxy-1-(4-phenoxybutyl)piperidine;4-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethoxy)phenoxy)ethyl)piperidine;4-(4-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;4-(4-chlorophenoxy)-4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine;5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine;2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-5-(trifluoromethyl)pyridine;4-(4-chlorophenoxy)-4-methyl-1-(2-(4-(methylsulfonyl)phenoxy)ethyl)piperidine;1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethan-1-one;1-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)ethan-1-ol;2-(4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)phenyl)propan-2-ol;4-(4-chlorophenoxy)-1-(2-(4-fluorophenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(4-chlorophenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-4-methyl-1-(2-(p-tolyloxy)ethyl)piperidine;2-((4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)pyridine;4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(3-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-(methylsulfonyl)phenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine;1-(2-(5-chloro-2-(trifluoromethyl)phenoxy)ethyl)-4-(4-chlorophenoxy)-4-methylpiperidine;5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)thiazole;6-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)benzo[d]oxazole;7-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3,4-dihydroquinolin-2(1H)-one;4-(benzyloxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine;3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-4-(trifluoromethyl)pyridine;4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-3-(trifluoromethyl)pyridine;3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)pyridine;2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-N-(2-(trifluoromethyl)phenyl)acetamide;N-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-2-(trifluoromethyl)aniline;N-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-N-methyl-2-(trifluoromethyl)aniline;N-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-N-(2-(trifluoromethyl)phenyl)acetamide;1-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-8-(trifluoromethyl)quinolin-2(1H)-one;2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-8-(trifluoromethyl)quinolone;4-(4-chlorophenoxy)-1-(2-(cyclohexyloxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidine;1-(2-(2-fluorophenoxy)ethyl)-4-methyl-4-phenoxypiperidine;1-(2-(2-chlorophenoxy)ethyl)-4-methyl-4-phenoxypiperidine;4-methyl-4-phenoxy-1-(2-(o-tolyloxy)ethyl)piperidine;1-(2-(2-ethylphenoxy)ethyl)-4-methyl-4-phenoxypiperidine;1-(2-(2-isopropylphenoxy)ethyl)-4-methyl-4-phenoxypiperidine;1-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one;4-methyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;4-methyl-4-phenoxy-1-(2-(3-(trifluoromethyl)phenoxy)ethyl)piperidine;4-methyl-4-phenoxy-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidine;1-(2-(5-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methyl-4-phenoxypiperidine;1-(2-(4-fluoro-2-(trifluoromethyl)phenoxy)ethyl)-4-methyl-4-phenoxypiperidine;4-methyl-4-phenoxy-1-(2-(2-(trifluoromethoxy)phenoxy)ethyl)piperidine;1-(2-(2-methoxyphenoxy)ethyl)-4-methyl-4-phenoxypiperidine;4-methyl-1-(2-(2-(methylsulfonyl)phenoxy)ethyl)-4-phenoxypiperidine;2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)benzonitrile;N,N-dimethyl-2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)aniline;2-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)pyridine;4-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)pyridine;1-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethyl)pyridin-2(1H)-one;4-methyl-1-(2-(naphthalen-1-yloxy)ethyl)-4-phenoxypiperidine;4-(2-(4-methyl-4-phenoxypiperidin-1-yl)ethoxy)-1H-indole;2-((4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)oxy)pyridine;4-(2-chlorophenoxy)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;(1R,3r,5S)-3-methyl-3-phenoxy-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octane;(1R,3s,5S)-3-methyl-3-phenoxy-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octane;1-(4-chlorophenyl)-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octane;2,4,6-trimethyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;4-methyl-1-(2-methyl-1-(2-(trifluoromethyl)phenoxy)propan-2-yl)-4-phenoxypiperidine;4-methyl-4-phenoxy-1-(1-(2-(trifluoromethyl)phenoxy)propan-2-yl)piperidine;4-methyl-4-phenoxy-1-(3-(2-(trifluoromethyl)phenyl)propyl)piperidine;4-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)-2-(2-(trifluoromethyl)phenyl)butan-2-ol;3-(4-methyl-4-phenoxypiperidin-1-yl)-1-(2-(trifluoromethyl)phenyl)propan-1-one;1-phenyl-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octane;1-phenyl-7-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,7-diazaspiro[3.5]nonane;1-(4-chlorophenyl)-7-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,7-diazaspiro[3.5]nonane;1-(4-chlorophenyl)-7-(2-(2-fluorophenoxy)ethyl)-1,7-diazaspiro[3.5]nonane;1-(4-chlorophenyl)-8-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-1,8-diazaspiro[4.5]decane;1-(4-chlorophenyl)-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,8-diazaspiro[4.5]decane;N,4-dimethyl-N-phenyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-amine;1′-(2-(2-(trifluoromethyl)phenoxy)ethyl)-3H-spiro[benzofuran-2,4′-piperidine];4-(hydroxy(phenyl)methyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol;2,2-dimethyl-4-phenyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-1,3-dioxa-8-azaspiro[4.5]decane;(4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)(phenyl)methanone;(4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)(phenyl)methanol;3-(4-chlorophenoxy)-3-methyl-1-(2-phenoxyethyl)piperidine;3-(4-chlorophenoxy)-3-methyl-1-(2-methyl-1-phenoxypropan-2-yl)piperidine;3-(4-chlorophenoxy)-1-(2-(2-fluorophenoxy)ethyl)-3-methylpiperidine;3-(4-chlorophenoxy)-1-(2-(2-chlorophenoxy)ethyl)-3-methylpiperidine;5-(2-(3-(4-chlorophenoxy)-3-methylpiperidin-1-yl)ethoxy)benzo[d]thiazole;3-methyl-1-(2-phenoxyethyl)-3-(3-(trifluoromethyl)phenoxy)piperidine;1-(2-(2-fluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine;1-(2-(2-chlorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine;4-methoxy-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol;3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-3-ol;(1R,3r,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol;(1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol;3-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)pyrrolidin-3-ol;4-methyl-1-(3-(2-(trifluoromethyl)phenoxy)propyl)piperidin-4-ol;4-methyl-1-(2-(4-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol;4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-ol;4-methyl-1′-(2-(trifluoromethyl)phenyl)-[1,3′-bipiperidin]-4-ol;1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-ol;4-methyl-1-(2-phenoxyethyl)piperidin-4-ol;1-(2-(2-fluorophenoxy)ethyl)-4-methylpiperidin-4-ol;1-(2-phenoxyethyl)-3-phenylpyrrolidin-3-ol;1-(2-(2,5-difluorophenoxy)ethyl)-3-methyl-3-(3-(trifluoromethyl)phenoxy)piperidine;and stereoisomers, racemates, tautomers, polymorphs, hydrates, solvates,and pharmaceutically acceptable salts thereof.
 41. The compound of claim1, selected from the group consisting of:3-(4-chlorophenoxy)-1-(2-(3-fluorophenoxy)ethyl)-3-methylpyrrolidine;1′-(2-phenoxyethyl)-3H-spiro[benzofuran-2,3′-pyrrolidine];3-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)pyridine;4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)pyridine;5-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-2-(trifluoromethyl)phenol;4-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)benzonitrile;1-(2-((1H-pyrazol-4-yl)oxy)ethyl)-4-(4-chlorophenoxy)-4-methylpiperidine;1-(2-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethoxy)-5-fluorophenyl)ethan-1-one;4-(4-chlorophenoxy)-1-(2-(2-methoxyphenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(4,5-difluoro-2-methoxyphenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(5-fluoro-2-isopropoxyphenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-1-(2-(4-fluoro-2-isopropoxyphenoxy)ethyl)-4-methylpiperidine;4-(4-chlorophenoxy)-4-isopropyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;4-(4-chlorophenoxy)-4-ethynyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;4-ethynyl-4-phenoxy-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;1-(2-(4-(4-chlorophenoxy)-4-methylpiperidin-1-yl)ethyl)-3-(trifluoromethyl)pyridin-2(1H)-one;(1R,3s,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol;(1R,3r,5S)-3-methyl-8-(2-(2-(trifluoromethyl)phenoxy)ethyl)-8-azabicyclo[3.2.1]octan-3-ol;N,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxamide;N, 4-dimethyl-1-(2-phenoxyethyl)piperidine-4-carboxamide;1-(2-(2-fluorophenoxy)ethyl)-N,4-dimethylpiperidine-4-carboxamide;1-(2-(2-methoxyphenoxy)ethyl)-N,4-dimethylpiperidine-4-carboxamide;1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,4-dimethylpiperidine-4-carboxamide;N-cyclopropyl-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidine-4-carboxamide;1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methyl-N-phenylpiperidine-4-carboxamide;(S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N,N,4-trimethylpiperidine-4-carboxamide;(S)-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)(pyrrolidin-1-yl)methanone;(S)-1-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-N-methylmethanamine;(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide;(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)cyclopropanecarboxamide;(S)—N-(1-((7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide;(S)—N-(1-((7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)acetamide;(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-2,2,2-trifluoroacetamide;(S)—N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-methylpiperidin-4-yl)-N-methylacetamide;(4-(4-chlorobenzyl)-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-yl)methanol;4-(4-chlorobenzyl)-4-methyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine;1-(4-chlorophenyl)-6-(2-(2-(trifluoromethyl)phenoxy)ethyl)-6-azaspiro[2.5]octane;N-cyclohexyl-N,4-dimethyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidin-4-amine;4-methyl-N-phenyl-1-(2-(2-(trifluoromethyl)phenoxy)ethyl)piperidine-4-carboxamide;1-(2-(2-fluorophenoxy)ethyl)-4-methyl-N-phenylpiperidine-4-carboxamide;and stereoisomers, racemates, tautomers, polymorphs, hydrates, solvates,and pharmaceutically acceptable salts thereof.
 42. (canceled)
 43. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof, and one or more pharmaceuticallyacceptable excipients or carriers.
 44. A method of modulating D2receptor activity, comprising administering a compound of claim 1, or apharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof.
 45. (canceled)
 46. A method oftreating or preventing a disease or disorder in which modulation of D2receptors plays a role, comprising administering to a subject in needthereof a therapeutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt, stereoisomer, racemate, tautomer,polymorph, hydrate, or solvate thereof, in combination with apharmaceutically acceptable excipient or carrier. 47-54. (canceled) 55.A method of treating or preventing a disease or disorder in whichmodulation of D2 receptors plays a role, comprising administering to asubject in need thereof a therapeutically effective amount of aselective β-arrestin antagonist.
 56. A method of treating or preventinga disease or disorder in which modulation of D2 receptors plays a role,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound which is a β-arrestin antagonist and acAMP agonist, or a pharmaceutically acceptable salt, stereoisomer,racemate, tautomer, polymorph, hydrate, or solvate thereof. 57-62.(canceled)